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Anuradha College of Pharmacy, Chikhli, Buldana, Maharastra, India, 443201
BCS Class II drugs are characterized by poor aqueous solubility and high permeability, which often leads to limited oral bioavailability due to insufficient dissolution in gastrointestinal fluids. Enhancing the solubility of such drugs is a crucial step in improving their pharmacokinetic and therapeutic performance. In recent years, increasing attention has been given to the use of herbal and natural excipients as safe, biodegradable, and cost-effective alternatives to synthetic excipients. Natural substances such as gums, mucilages, polysaccharides, and plant-derived surfactants have demonstrated significant potential in improving drug solubility through mechanisms including wettability enhancement, particle size reduction, and amorphous conversion. Along with conventional techniques such as solid dispersion, nanosizing, and lipid-based systems, herbal excipients offer a sustainable and patient-friendly approach for bioavailability enhancement. This review summarizes various solubility enhancement strategies with special emphasis on herbal excipients and their role in improving the oral bioavailability of BCS Class II drugs.
Solubility is an important parameter for achieving the desired drug concentration in the bloodstream, which is essential for a proper pharmacological response [1]. Drugs that are highly soluble generally show good oral absorption and, consequently, better bioavailability [2]. Quantitatively, solubility is defined as the concentration of solute in a saturated solution at a specific temperature, while qualitatively it describes the natural tendency of two or more substances to form a homogeneous molecular mixture [3]. Drug solubility, therefore, represents the maximum concentration of a drug that can dissolve in a given solvent under defined conditions such as pH, temperature, and pressure. Unlike dissolution rate—which varies depending on external factors and determines how quickly the drug becomes available for absorption—solubility in a saturated solution is a fixed property. A solubility chart further illustrates the behavior of ions, showing whether they remain dissolved in aqueous media or form precipitates.[3].
Solubility refers to the property of a solid, liquid, or gaseous substance (solute) to dissolve in a solid, liquid, or gaseous medium (solvent), forming a homogeneous solution. The solvent is most often a liquid, which may be either a pure substance or a mixture of liquids; in some cases, solid solutions can occur, while solutions in gases are rarely observed.?
Background of BCS class
The biopharmaceutical classification system (bcs) is a framework designed to categorize drugs based on their solubility and permeability characteristics, which are critical in determining their absorption and availability when taken orally. This system was developed to offer a structured method for drug formulation and to forecast drug behaviour within the gastrointestinal tract. It comprises four classes:
Class i: high solubility and high permeability.
Class ii: low solubility but high permeability.
Class iii: high solubility but low permeability.
Class iv: low solubility and low permeability.
Solubility refers to the property of a solid, liquid, or gaseous substance (solute) to dissolve in a solid, liquid, or gaseous medium (solvent), forming a homogeneous solution. The solvent is most often a liquid, which may be either a pure substance or a mixture of liquids; in some cases, solid solutions can occur, while solutions in gases are rarely observed. ?
The solubility of any substance depends mainly on the solvent, temperature, and pressure. Its extent is measured by the saturation concentration, the point at which additional solute can no longer increase the solution’s concentration. Solubility can vary greatly—from complete miscibility, such as ethanol in water, to very low solubility, such as silver chloride in water. Compounds that dissolve only to a small extent are commonly described as poorly soluble or even “insoluble”. At the molecular level, solubility takes place under dynamic equilibrium, where dissolution and the reverse process (phase separation, such as precipitation) occur simultaneously. When these processes proceed at equal rates, solubility equilibrium is achieved. In certain conditions, this balance can be surpassed, resulting in a supersaturated solution that remains metastable. USP and BP classify the solubility regardless of the solvent used, just only in terms of quantification and have defined the criteria given table.¹?
tabel.1
BCS class II drug characteristics
Employing innovative super disintegrants: such as ocimum gratissimum mucilage, to create fast dissolving tablets of aceclofenac, thereby improving drug disintegration time and dissolution rate
Solid dispersion techniques: like the use of peg 6000 and crospovidone in ternary solid dispersions of naproxen, have been effective in significantly boosting drug dissolution rate and oral bioavailability.
Adsorbents: like granulated fumed silica have been utilized to enhance ibuprofen solubility and dissolution characteristics, leading to increased drug solubility and dissolution rate.
Pegylation : of BCS class ii drugs such as raloxifene hydrochloride with high-molecular-weight polyethylene glycols has been found to enhance tablet dissolution rate and improve drug release characteristics.
lipid carriers: like niosomes, based on non-ionic surfactants, have shown promise in improving the solubility and bioavailability of BCS class ii drug¹?
Bhavna process:
Bhavana (levigation or wet grinding of single/compound powdered drugs with liquid media (i.e., juice/decoction/solution of plant, animal, or mineral origin)) is a unique process and probably the most extensively used pharmaceutical procedure of Ayurveda. Bhavana is also known as Samskara in Sanskrit, that is, transformation (Samskaro hi Gunantaradhanamuchyate) of the inherent attributes of a substance which leads to the addition of new properties or qualitative improvement. Bhavana carries the qualities and action (Guna-Karma) of liquid media with powdered drugs to be levigated; thus, in simple words, Bhavana corresponds to the impregnation of the properties of liquid media to the Bhavita material (drug material undergone Bhavana process). Thus, it presumably by change in potency (Gunantara), addition of new properties (Gunadhana), augmentation (Gunotkarsha), or reduction or removal of properties (Gunahani) [2, 3]. In the present scenario of globalization, all rational skeptics are engrossed in understanding this traditional pharmaceutical process of transformation. Ancient Indian sage Charaka in the context of describing the principles of pharmaceutics advocates Bhavana by expressing herbal juice (Svarasa) or herbal decoction (Kwatha) of the same drug or drugs with similar properties, and its uses are explained as quicker, augmented action with possible reduction in the required therapeutic dose of the drug under process [4]. Ayurveda literature is used as an authoritative search engine highlighting the importance of Bhavana in herbal and herbomineral drug possessing with multidimensional pharmaceutical and therapeutic implications (Figure 2). Likewise, in the Siddha system of Indian medicine, Bhavana with herbal juices is advocated to prepare highly potent, microfine, metal-based formulations named "Chunnam" akin to Ayurvedic metallomineral Bhasma (an Ayurvedic dosage form of incinerated ash/calx of metals/minerals) preparations.³?
Figure 1
Importance of solubility
Oral ingestion is the most convenient and most widely used method of drug delivery because of its ease of administration, high patient compliance, cost effectiveness, sterility restrictions and flexibility in dosage form design. Solubility is the essential rate limiting criterion for orally delivered drugs to acquire their required concentration in systemic circulation for pharmacological response. The two most frequent reasons for inadequate oral bioavailability are poor solubility and permeability. The poor bioavailability of oral dosage forms, on the other hand, is a major difficulty in their design. Therefore, for formulation scientists, the problem of solubility is a key concern.[7]
The US Food and Drug Administration (FDA) created the Biopharmaceutics Classification System (BCS). categorizes pharmaceuticals into four classes according on their solubility and permeability characteristics. Low solubility causes a soluble obstacle in Classes II and IV of the system, where the medication absorption process's rate-limiting phase is dissolution. The drugs are categorized by the Biopharmaceutical Classification System (BCS) according to their intestinal permeability and intrinsic solubility. Good intestinal permeability and solubility contribute to a drug's high bioavailability. The bioavailability of drugs with low solubility and permeability is dependent on their solubility and permeability, respectively. The majority of medications in the pharmaceutical industry today have poor solubility. Poor solubility has been effectively addressed by a number of solubility enhancement strategies.²?
Significance of solubility and dissolution rate enhancement
Enhancing the solubility and dissolution behavior of poorly water-soluble drugs is a key requirement for improving their absorption and overall therapeutic performance. Poor dissolution often limits the bioavailability and clinical effectiveness of such medications, making this a major challenge in drug development. Numerous studies have highlighted that increasing solubility and dissolution rates can significantly improve drug bioavailability. In this context, formulation strategies such as solid dispersions and nanocrystalline suspensions have demonstrated considerable success in accelerating drug dissolution and enhancing delivery efficiency 4,5,6. Collectively, these observations underline the critical importance of solubility and dissolution enhancement in pharmaceutical development and demonstrate the strong potential of these approaches to overcome absorption-related limitations associated with poorly water-soluble drugs.¹?
SOLUBILITY ENHANCEMENT:
Enhancing the dissolution and absorption of poorly water-soluble medications is essential for addressing challenges that limit their effectiveness. Numerous studies have highlighted the importance of enhancing these properties to improve the bioavailability of these drugs. Techniques such as solid dispersion and nanocrystal line suspensions have effectively enhanced dissolution rates, thereby improving delivery and potential clinical outcomes of poorly soluble drugs. These findings highlight the crucial significance of enhancing solubility and dissolution rates in pharmaceutical development, particularly for poorly water-soluble drugs, and emphasize the potential of these methods in improving drug absorption. (1) Various methods are employed to improve the solubility of drugs that have low solubility. These methods include reducing particle size, adjusting pH, using hydrotropes, complexation techniques, creating solid dispersions, forming salts, emulsification, co-crystallization, and the production of Nano-crystals.²³
In vivo technique
The assessment of in-vivo pharmacokinetics (pk) is pivotal in gauging the effectiveness of drug formulations that boast enhanced solubility and dissolution characteristics. These evaluations are instrumental in deciphering how these improvements manifest in terms of heightened bioavailability and therapeutic effectiveness in living organisms. Numerous methodologies have been devised to scrutinize the pk profile of such formulations, encompassing a range of approaches and techniques.²?
IN-vitro to in-vivo correlation (IVIVC): The concept of in-vitro to in-vivo correlation entails employing an in vitro model that accurately replicates the conditions within a living organism to forecast the performance of a drug formulation in either animal subjects or humans. IVIVC facilitates the estimation of in vivo dissolution rates based on in vitro data, thereby aiding in the refinement of dosage forms and minimizing reliance on animal experimentation.²?
Animal models: Utilizing animal models continues to be a prevalent method for investigating the impacts of improving solubility and dissolution on drug absorption. This approach typically involves studying various species such as rodents (e.g., mice, rats) and larger mammals (e.g., dogs, pigs).¹?
Human studies: Particularly clinical trials employing human participants, are widely regarded as the most reliable method for assessing the safety and effectiveness of new medications. Nevertheless, conducting such trials may not always be viable due to financial constraints, time limitations, and ethical concerns. Consequently, alternative approaches like micro dosing are being investigated to obtain data on the pharmacokinetic profiles of innovative formulations without subjecting individuals to undue risks.²?
Pharmaco metrics modelling: Involves the integration of quantitative biomedical information with mathematical and statistical approaches to enhance comprehension of drug mechanisms across different domains such as drug distribution and response. Through pharmacometric modeling, researchers can explore intricate connections among drug concentration, exposure, and efficacy, thereby gaining valuable insights into how improvements in solubility and dissolution influence drug pharmacokinetic profiles.It's important to acknowledge that while in-vivo pharmacokinetic assessments offer valuable insights into the effectiveness of formulations enhanced for solubility and dissolution, they frequently demand considerable resources and may entail risks linked to animal testing or clinical studies. Consequently, there has been increasing interest in the creation of more streamlined and less intrusive alternatives, such as computational modeling and sophisticated in vitro methodologies. Importance of pharmacokinetic evaluation in drug development.²?
Dose optimization: pk studies play a crucial role in optimizing dosing regimens for drugs by elucidating how the body metabolizes a compound. This knowledge enables the development of dosing schedules that balance therapeutic efficacy with minimal risk of toxicity.³¹
Bioavailability assessment: pk assessment offers vital understanding regarding the degree and speed with which a drug enters the bloodstream. This data is critical in evaluating the bioavailability of a drug, which directly influences its effectiveness in therapy. ¹?
Safety and tolerability: Understanding how a drug is metabolized and eliminated through pharmacokinetic (pk) studies is crucial for identifying any potential safety issues and determining the appropriate safety margins. This knowledge is essential to ensure that the drug is tolerated well and does not produce unwanted effects when administered at therapeutic levels. ²²
Drug-drug interactions: Pharmacokinetic (pk) assessments are instrumental in recognizing possible interactions between the experimental drug and other pharmaceuticals. Grasping the impact of a novel compound on the pk characteristics of concurrently administered drugs is pivotal for safeguarding patient well-being and preventing unforeseen adverse responses.²?
Predicting variability: Pharmacokinetic (pk) investigations contribute to comprehending the diversity in drug reactions across various patient groups, such as differing age brackets or individuals with particular health conditions. Such insights are critical for customizing dosage plans to achieve the best possible results across a wide range of patient demographic.²¹
Regulatory requirements: Regulatory agencies mandate thorough pharmacokinetic (pk) information to evaluate the safety and effectiveness of emerging pharmaceuticals. Pk assessments play a vital role in the submission process for investigational new drug (ind) applications and new drug approvals. IN conclusion, pharmacokinetic assessment plays a crucial role in the process of drug development. It guides the optimization of dosages, evaluates bioavailability, ensures safety, identifies interactions, predicts variability, and meets regulatory standards. Through illuminating the behavior of drugs within the body, pharmacokinetic studies substantially contribute to the successful advancement and eventual approval of novel pharmaceutical products.³³
LIMITATIONS OF SOLUBILITY ENHANCEMENT .
Stability Problem: It has physical as well as chemical instability; many approaches, such as especially nanoparticles and amorphous forms, face aggregation mechanism or even recrystallization may also lessen the impact of solubility improvement.
Scalability: Scalability from laboratory scale to industrial production is difficult with nanoparticles being complex in terms of high-priced raw materials and dedicated equipment.
Toxicity: Nanoparticles, as well as some excipients, carry induction hazards in which cellular uptake and immune responses, cause potential side effects.
Regulatory Challenges: Not having a standardization of guidelines for nanomaterials has brought delays in authorization and regulatory ambiguity.
Cost: Development of the advanced solubility techniques like Nano carriers increases the production cost; hence its commercialization fades.
Long-Term Effects: Little safety and environmental impact-relevant data are available for such new methodologies such as nanoparticles.
Formulation Complexity: Formulations with multiple excipients to produce effective formulations are quite complex and such might weaken the stability or efficacy of the drug.²?
REFERENCES
Tanisha Kale, Unmesh Joshi, Hemant Sawarkar, Dr. K. R. Biyani, Review on Application of Bhavana Process for Solubility Enhancement of Poorly Water Soluble Drug, Int. J. of Pharm. Sci., 2026, Vol 4, Issue 5, 2992-3001. https://doi.org/10.5281/zenodo.20158003
10.5281/zenodo.20158003