Department of Pharmaceutics, D. K. Patil Institute of Pharmacy, Loha Nanded India 431708
The solubility of an active pharmaceutical ingredient (API) plays a pivotal role in determining its bioavailability after oral administration. Poor aqueous solubility, common among many new drug candidates, can lead to inconsistent absorption, necessitating higher doses and complex formulations, which in turn increase development costs. The Biopharmaceutical Classification System (BCS) highlights this challenge, especially for Class II and Class IV drugs, which exhibit low solubility. To address these issues, recent advancements have focused on enhancing solubility through innovative formulation techniques. Amorphous Solid Dispersions (ASDs), produced via Hot-Melt Extrusion (HME) and Spray Drying, improve dissolution by maintaining drugs in a high-energy amorphous state. Nanosuspensions increase surface area and dissolution rate by reducing particle size. Lipid-Based Drug Delivery Systems (LBDDS), including Self-Microemulsifying Drug Delivery Systems (SMEDDS), enhance solubility through lipid solubilization mechanisms. Other emerging strategies include co-crystals, which modify the drug’s crystalline structure to improve solubility, and mesoporous silica materials that offer high surface area and controlled release properties. These technologies are gaining traction in the pharmaceutical industry due to their effectiveness and scalability. This review aims to critically evaluate these modern approaches, focusing on their mechanisms, manufacturing feasibility, and current adoption trends over the past decade.
The solubility of a drug in aqueous media is a critical physicochemical property that fundamentally dictates its therapeutic efficacy. For an orally administered drug to exert its systemic effect, it must first dissolve in the gastrointestinal fluids to be absorbed across the biological membranes and reach the systemic circulation. This process, known as drug bioavailability, is often rate-limited by dissolution for compounds with poor aqueous solubility.
Importance of Solubility in the Biopharmaceutical Classification System (BCS)
The Biopharmaceutical Classification System (BCS) classifies drugs into four categories based on their aqueous solubility and intestinal permeability [1]. BCS Class II drugs exhibit low solubility but high permeability; their absorption is typically dissolution rate-limited [6] . BCS Class IV drugs suffer from both low solubility and low permeability, posing the most significant challenge in formulation development [7]. For BCS Class II drugs, improving the dissolution rate (i.e., solubility) is a primary focus for enhancing bioavailability. The BCS framework is widely used in pharmaceutical development and regulation to waive in vivo bioequivalence studies [1].
Challenges Posed by Low Solubility on Drug Development and Patient Compliance
Low aqueous solubility presents numerous hurdles throughout the drug development lifecycle: limited and variable absorption, resulting in unacceptably low or highly variable systemic drug concentrations [3] . This often necessitates higher doses to achieve the desired therapeutic concentration, potentially increasing production costs and the risk of dose-related side effects [4]. Furthermore, developing conventional dosage forms for poorly soluble drugs is challenging, leading to complex and expensive formulation strategies [4, 5]. It is estimated that up to 70%of new chemical entities (NCEs) being discovered possess poor water solubility, underscoring the magnitude of this problem in modern pharmaceutical research [3, 5].
Recent Trends and Innovations in Solubility Enhancement Techniques
The field of solubility enhancement is rapidly evolving, moving toward sophisticated, often nanotechnology-based, and solid-state manipulation methods.
Figure 1: Solubility Enhancement Techniques [8]
Classification of Poorly Water-Soluble Drugs
BCS Class II and IV Drugs: Characteristics and Challenges
BCS Class II drugs are characterized by low solubility but high permeability. Their absorption is typically dissolution rate-limited, making the enhancement of solubility and dissolution rate the primary formulation goal [6]. In contrast, Class IV drugs have both low solubility and low permeability, representing the most challenging class as they require simultaneous strategies to address both low dissolution and poor membrane transport [7].
Impact of Poor Solubility on Drug Dissolution and Absorption
Poor solubility directly impedes drug absorption by several mechanisms. First, the Noyes-Whitney equation dictates that the dissolution rate is proportional to the drug's saturation solubility results in a slow dissolution, meaning the drug may pass through the gastrointestinal tract before adequate dissolution [8]. Second, this incomplete dissolution leads to incomplete absorption, resulting in low and variable systemic drug concentrations and reduced bioavailability [4]. Third, poorly soluble drugs are highly susceptible to variations in ph and food effects, leading to significant inter-patient variability in drug response [9].
MATERIALS AND METHODS
Particle Size Reduction
The goal is to increase the effective surface area exposed to the dissolution medium, thus increasing the dissolution rate [8]. Micronization reduces particle size to the micrometer range (approx 1 - 10 nm) via jet milling, a standard and cost-effective method [10]. Nanonization (Nanocrystallization) further reduces particle size to the nanometer range (approx. 10 – 1000 nm), significantly increasing the surface area [11]. Methods include Wet Bead Milling (Top-Down), which uses high-shear stress to break down coarse drug particles, and High-Pressure Homogenization (HPH), which forces the suspension through a narrow gap under high pressure [11, 12].
Solid Dispersions
A Solid Dispersion (SD) involves dispersing the drug in an inert carrier matrix [13]. The drug is often converted to its high-energy amorphous state. Polymeric carriers (e.g., HPMC-AS) are essential for inhibiting drug molecule mobility, which prevents the drug's recrystallization (often called the "parachute" effect) during storage and in vivo exposure [13].
Salt Formation and Co-crystallization
These are chemical or crystal engineering modifications. Salt Formation involves reacting an ionizable drug (acid/base) with a counter-ion. Salt forms have dramatically higher dissolution rates because they change the pH of the diffusion layer surrounding the particle, favoring dissolution [14]. Co-crystallization is the creation of a multi-component crystal of an API and a neutral co-former linked by non-covalent bonds. This alters the crystal lattice energy, improving dissolution properties, particularly for non-ionizable drugs [15].
Cosolvency and Hydrotropy
These are liquid-state techniques using auxiliary agents. Cosolvency utilizes water-miscible organic solvents (e.g., ethanol, PEG) to reduce the polarity of the aqueous solution, increasing the drug's solubility [16]. Hydrotropy uses high concentrations (10% w/v) of hydrotropes (e.g., sodium benzoate) to form soluble aggregates with the drug, increasing apparent solubility without micelle formation [17].
Nanotechnology-Based Approaches
Nanocrystals are pure drug nanoparticles that offer greatly enhanced dissolution due to increased surface area and higher saturation solubility based on the Ostwald-Freundlich relationship [10]. Polymeric Micelles are self-assembled structures where amphiphilic block copolymers encapsulate the hydrophobic drug in a non-polar core. Similarly, Dendrimers are highly branched polymers with internal cavities that solubilize the drug, resulting in high solubility enhancement and potential for targeted delivery [18, 19].
Self-Emulsifying Drug Delivery Systems (SEDDS)
SEDDS are isotropic mixtures of oil, surfactant, and co-solvent that spontaneously form fine oil-in-water emulsions (e.g., microemulsions, nanoemulsions) upon contact with fluid [20]. This presents the drug in a pre-dissolved state, entirely bypassing the dissolution step for BCS Class II drugs. This is utilized in oral delivery for highly lipophilic drugs, often leveraging lymphatic transport to avoid hepatic first-pass metabolism, enhancing bioavailability and reducing variability [21].
Supercritical Fluid Technology
Supercritical Fluid Technology is used to manipulate particle formation. Processes like Rapid Expansion of Supercritical Solutions (RESS) and Supercritical Anti-Solvent (SAS) precipitate the drug, yielding highly pure, ultra-fine nanoparticles with a narrow size distribution, leading to enhanced dissolution [22, 23]. A major advantage is the easy removal of the CO, resulting in a solvent-free product [23].
Liquisolid Systems
This technique converts a liquid medication (drug dissolved in a non-volatile, water-miscible solvent) into a free-flowing, compressible powder using porous carrier and coating materials (e.g., silica) [24]. The drug is molecularly dispersed in the liquid film covering the carrier particles. Upon contact with water, the drug is released in an already dissolved state, significantly enhancing the dissolution rate [25] .
Machine Learning and Computational Approaches
Machine Learning (ML) models, trained on large datasets, are used to rapidly and accurately predict the solubility and bioavailability of new API candidates, guiding early-stage selection and structural modification [26] . Furthermore, Molecular Dynamics (MD) simulations are employed to understand drug-excipient interactions, predicting the stability of amorphous forms and optimizing the formulation ratio, thereby minimizing trial-and-error experimental work [27].
Figure 2: Enhancement of Solubility and Oral Bioavailability [26]
Comparative Analysis of Techniques
Table 1: Comparative Analysis of Techniques
|
Criteria |
Conventional (Micronization, Salt Forms) |
Advanced (ASDs, Nanosuspensions, SEDDS) |
Citation |
|
Effectiveness |
Moderate, limited by crystalline properties. |
High to Very High (e.g., ASDs generate supersaturation, SEDDS bypass dissolution). |
[28] |
|
Stability |
Highest physical stability (crystalline state). |
Physically challenged (amorphous/nanocrystalline state prone to recrystallization/aggregation). |
[14, 12] |
|
Scalability |
High (mature technology). |
Highly scalable (HME is continuous, SEDDS is simple mixing). |
[29, 30] |
|
Cost |
Low capital and operational costs. |
High capital investment (HME, HPH equipment). |
[29] |
|
Industrial Use |
Very High. |
High and increasing (e.g., numerous approved ASD and SEDDS products). |
[30] |
The enhancement technique must be rationally matched to the drug's properties (e.g., thermal stability) [31]. For high-energy forms (ASDs, Nanocrystals), robust stabilization (e.g., polymer selection) is the most critical factor for commercial viability [13]. Finally, application of Quality by Design (QbD) principles is a best practice to define and control Critical Process Parameters (CPPs) for sensitive advanced manufacturing techniques, ensuring batch-to-batch consistency and scalability [32, 43]. Recent studies and industrial practices have focused on the following materials and methodologies to enhance the solubility of poorly water-soluble drugs [39,42]
1. Amorphous Solid Dispersions (ASDs)
2. Nanosuspensions
3. Lipid-Based Drug Delivery Systems (LBDDS)
4. Co-crystals
5. Mesoporous Silica Carriers
Table 2: Comparative Table of Solubility Enhancement Techniques
|
Technique |
Key Materials Used |
Methodology |
Advantages |
Limitations |
|
Amorphous Solid Dispersions |
PVP, HPMC, Soluplus |
HME, Spray Drying |
High drug loading, scalable |
Physical instability |
|
Nanosuspensions |
Surfactants, stabilizers |
Homogenization, Milling |
Enhanced dissolution, fast absorption |
Agglomeration risk, complex processing |
|
SMEDDS (LBDDS) |
Lipids, surfactants, co-solvents |
Self-emulsification |
Improved oral bioavailability |
Limited to lipophilic drugs |
|
Co-crystals |
API + co-formers |
Grinding, Solvent Evaporation |
Improved solubility and stability |
Co-former selection critical |
|
Mesoporous Silica Systems |
MCM-41, SBA-15 |
Solvent loading, melt method |
High surface area, controlled release |
Drug leaching, scalability issues |
Regulatory Guidelines for Solubility Enhancement Techniques
Successful solubility enhancement can potentially lead to a Biowaiver for in vivo bioequivalence studies, particularly for Class II drugs that exhibit very rapid dissolution [33]. However, advanced systems often use novel or non-compendial excipients (e.g., new polymers, surfactants), requiring extensive regulatory data on the excipient's safety, function, and potential toxicity [34]. Furthermore, rigorous validation of complex processes like HME and HPH is required to demonstrate control over Critical Quality Attributes (CQAs), such as amorphous content and particle size [30, 34]. The high concentrations of surfactants and co-solvents in SEDDS must be justified and safety-reviewed to prevent potential irritation or systemic toxicity [35]. The manufacturing processes must not induce chemical degradation, and the enhanced solubility should be managed to prevent localized supersaturation that could cause irritation or precipitation in vivo [31].
Challenges in Regulatory Approval of Novel Formulations
Providing definitive long-term stability data to guarantee no recrystallization of under stress conditions remains a key regulatory hurdle [30]. Similarly, precise and consistent control over the size and stability of nanoparticles (zeta potential, size distribution) is mandatory to ensure reproducible in vivo performance [20, 34]. Finally, regulatory bodies stringently require in vitro dissolution testing to be conducted in biorelevant media (e.g., FaSSIF/FeSSIF) to accurately predict in vivo behavior for advanced formulations [33].
Case Studies and Applications
Successful examples of solubility enhancement in drug development underscore the transformative potential of these techniques [28].
FUTURE PERSPECTIVES
The future of solubility enhancement will be defined by its integration with advanced computing, continuous manufacturing, and personalized medicine.
Trends in Personalized Medicine and their Impact on Solubility Enhancement
3D Printing (Additive Manufacturing), coupled with derived filaments, will enable personalized medicine by allowing for rapid, tailored dosages and precisely engineered release profiles, which can customize to individual absorption variability [37]. Furthermore, AI/ML is being developed to dynamically optimize entire formulation spaces, predicting the optimal technology and component ratios for stability and efficacy before any physical formulation begins ("rational design") [26].
Potential of Combination Therapies and Novel Drug Delivery Systems
Next-generation systems will focus on Multifunctional Nanocarriers, such as evolving Liposomes and Polymeric Micelles [18, 45]. These are being designed as targeted platforms that not only solubilize the drug but also include ligands for active targeting to specific tissues, simultaneously improving efficacy and reducing off-target toxicity [45]. Research is also exploring the use of Co-crystals as precursors in HME to control the dissolution and crystallization process in stabilized amorphous systems [15]
Research Gaps and Areas for Future Exploration
The primary scientific gap remains the accurate in silico prediction of drug performance in the complex GI tract, accounting for variability in bile salts, fluid volume, pH, and microbiota, which is necessary to replace static in vitro tests [9, 33]. Furthermore, there is a need for the development of dual-action systems that effectively address both low solubility and poor permeability for BCS Class IV drugs [7]. Finally, the industrial transition to fully continuous manufacturing (e.g., continuous HPH) requires further Process Analytical Technology to ensure real-time quality assurance [23, 43].
RESULT
Recent advancements in solubility enhancement have yielded promising outcomes across multiple formulation strategies. Key findings include:
DISCUSSION
The results underscore the effectiveness of modern solubility enhancement techniques in overcoming bioavailability challenges associated with poorly water-soluble drugs. Each approach offers unique advantages:
Overall, these technologies are increasingly adopted in the pharmaceutical industry, with several commercial products now leveraging these strategies. Continued research into hybrid systems (e.g., lipid-nano hybrids, co-crystal-ASDs) and predictive modeling for formulation design will further advance this field.
CONCLUSION:
The problem of poorly water-soluble drugs continues to challenge drug development, yet it has spurred immense innovation. Technologies like $\text {ASDs}$, Nanosuspensions, and SEDDS have provided reliable commercial solutions for numerous challenging APIs. The core insight is that overcoming poor solubility requires shifting the drug into a high-energy state (amorphous or nanocrystalline) or bypassing dissolution entirely. The critical hurdle for these advanced systems remains the long-term physical stability of the high-energy form against recrystallization or aggregation. Continued investment in Machine Learning for rational design and the mastery of continuous manufacturing techniques will ensure that a molecule's therapeutic potential is never limited by its physical properties. The future of drug development for poorly water-soluble compounds is moving toward precision pharmaceutics, delivering safer, more effective, and patient-centric therapies.
REFERENCE
Mukta Jagtap*, Recent Trends in Solubility Enhancement Techniques for Poorly Water-Soluble Drugs, Int. J. Sci. R. Tech., 2025, 2 (11), 222-231. https://doi.org/10.5281/zenodo.17560145
10.5281/zenodo.17560145
