When Poor Solubility Becomes a Problem: Challenges and Strategies in Modern Drug Development

May 15, 2025 11:36 CST Updated 11:36

AstraZeneca

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GSK

Pharmaceutical R&D Manufacturer

When solubility becomes an issue, the bioavailability of drug absorption in the body may be problematic;

When solubility becomes an issue, drug absorption in the body may vary between individuals and within the same individual;

When solubility becomes an issue, the efficacy of the drug is greatly reduced;

When solubility becomes an issue, the drug may exhibit toxic side effects;

When solubility becomes an issue, the difficulty of formulation development increases;

When Solubility Becomes an Issue......

Abstract

Drug absorption, along with sufficient and reproducible human bioavailability and/or pharmacokinetic profiles, is now considered one of the major challenges for orally administered new drugs. This issue became particularly prominent in the mid-1990s when drug discovery and medicinal chemistry shifted from wet chemistry to combinatorial chemistry and high-throughput screening. Considering that drug development timelines span 8-12 years, the apparent R&D productivity gap, determined by the number of products currently in late-stage clinical development, is a result of drug discovery and formulation development from the late 1990s—during the early and thriving period of combinatorial chemistry and high-throughput screening. Alongside the implementation of these new technologies, extensive knowledge has been accumulated regarding biological factors such as transporters, metabolic enzymes, and efflux systems, as well as physicochemical properties like drug crystal structure and salt formation that influence oral bioavailability. Research tools and technologies have been, are being, and will continue to be developed to evaluate the impact of these factors on drug absorption in new chemical entities.

The meeting paid special attention to compounds with poor solubility in analytical evaluation and oral absorption prediction,Raw MaterialsSelection, Materials andFormulaImpact of Strategies and Development. A detailed discussion of existing tools and technologies, their potential applications throughout the drug development process, and further research directions to overcome existing gaps and influence the properties of these drugs.

1. Introduction

With the introduction of combinatorial chemistry and high-throughput screening, the properties of new chemical entities have shifted towards higher molecular weight and increased lipophilicity, resulting in reduced water solubility (Lipinski et al., 1997; Lipinski, 2000).

The solubility in different solvents is an inherent material characteristic of a specific molecule. To achieve pharmacological activity, the molecule must generally exhibit a certain level of solubility in physiological intestinal fluids to be present in a dissolved state at the absorption site. Water solubility is the primary indicator of intestinal fluid solubility and its potential contribution to bioavailability issues.

During the drug development process, molecules are screened in nanomolar receptor assays. Molecules with the best receptor binding are selected for further preclinical studies, leading to the synthesis of more drugs.

At this stage, solubility is already crucial, as the estimation of solubility for poorly defined drug components aids in their pharmacological and toxicological analysis.

When first entering the human body, sufficient and good solubility becomes more critical. From now on, the solubility or dissolution of the active pharmaceutical ingredient (API) or formulated API in various biophysiological media is expected to be reproducible and remain unchanged during final development and upon market release. Today, the entire scientific community generally recognizes that drug solubility, particularly the solubility of water-soluble drugs, is an issue in the drug discovery process as well as in both early- and late-stage drug development, thus requiring resolution early in the compound design and optimization process.

The solubility or dissolution rate of active pharmaceutical ingredients (APIs) can primarily be altered at two levels through material engineering or formulation methods of the API. Regardless of the approach taken to enhance or modifyPilotSolubility and/or dissolution of substancesOut, it needs to be scaled up to a commercially viable process in the later stages of development.

Besides the water solubility of a drug, its permeability is the second key aspect of oral bioavailability.

BiologyPharmaceuticsThe Biopharmaceutics Classification System (BCS), introduced in the mid-1990s, categorizes drugs based on their aqueous solubility and membrane permeability (Amidon et al., 1995). Active pharmaceutical ingredients that can enhance bioavailability through improved solubility are classified as Class 2 (low solubility/high permeability) and Class 4 (low solubility/low permeability). Particularly for Class 2 substances, improving solubility is part of a strategy to enhance oral bioavailability.

The BCS classification takes into account the required dose, as low-dose drugs will be fully dissolved in the gastrointestinal fluid and absorbed, whereas high-dose drugs with similar water solubility will not. To broadly describe "solubility," the pharmacopeia (USP) uses seven different solubility expressions, as shown in Table 1. The European Pharmacopoeia uses a similar definition of solubility, but the characteristic of being "practically insoluble" is not clearly specified (European Pharmacopoeia 5.0).

When reviewing product launches between 1995 and 2002, 14 of the 100 substances were classified as Class I, 12 as Class II, 28 as Class III, and 46 as Class IV substances (Mehta, 2002). If an active pharmaceutical ingredient exhibits poor water solubility, product development will need to focus on studying various other characteristics of the active pharmaceutical ingredients, such as their physicochemical and biological properties.PharmaceuticsCharacteristics and target doses to determine the potential impact of solubility on further product development. Currently, it is known that approximately 35-40% ofPilotThe water solubility of the substance at pH 7 is less than 10.μM or 5mg/ml, this figure is not expected to change in the future.

2. Physical/Chemical Properties of Active Pharmaceutical Ingredients

Solubility is an intrinsic material property that can only be influenced by chemical modifications of the molecule itself, such as salt complexation or prodrug formation. In contrast, dissolution is an extrinsic material property that may be affected by various chemical, physical, or crystallographic means, such as complexation, particle size, surface properties, solid-state modifications, or solubilization enhancement formulation strategies.

Solubility is one of the key physicochemical parameters of a new molecule that needs to be assessed and understood early in the drug discovery and candidate selection process. Starting from the first batch of synthesized material, usually a few milligrams, the first series of analytical tests include the equilibrium solubility of the substance in a given solvent, as well as apparent or kinetic solubility, which reflects the concentration of the substance in solution under certain conditions. The value of equilibrium solubility is typically limited by the duration of the test, usually between 4 to 24 hours. The solubility and apparent solubility of a substance in aqueous systems depend on several factors (Table 2).

To identify potential issues with drug precipitation in the body, the solubility of the substance is required.Curve, rather than single-point determination. Particularly, the pH analysis of weakly basic salts is crucial because their solubility may vary in intestinal pH (typically pH 1-8), and pre-precipitation might occur. The pH analysis should be conducted in different biorelevant buffer systems to simulate the most common pharmaceutical salts in gastrointestinal fluids.CounterionHigh concentration. TheScreeningAllow detection of potential counterion exchange and formation of more stable/lower solubility molecular salts, which will lead to precipitation in vivo. pHCurveAlso provides basic guidance for selecting potential solubilization strategies.

In solubility analysis, the conversion of molecules to other salts or hydrates needs to be considered and evaluated. Different substance salts can be formed depending on the buffer system and its ionic strength. It is generally accepted that ionizable groups and possibleCounterionThe pKa values should differ by at least three units (Bowker, 2002). (Ampholytes exhibit a more complex solubilization process (a two-step reaction), including micelle formation at high ionic strength. Buffer salts and hydrates may possess different dissolution characteristics.) Therefore, various analytical methods have been developed to evaluate substances in solution or solid state (precipitates) (Giron and Grant, 2002). The analytical method for controlling substances in solution by pH is LC coupled with UV and MS. For solid-state analysis, techniques such as powder X-ray diffraction, energy-dispersive X-ray (EDX), Raman spectroscopy, infrared spectroscopy, microscopy (polarized light microscopy (PLM), environmental scanning electron microscopy (ESEM)), and thermal analysis are used.

Solubility analysis should include any other bioadjuvant solvents.OutMedia, such as simulated gastric fluid (SGF) with or without enzymes, fasted-state simulated intestinal fluid (FaSSIF) at pH 5.0 and 6.5, and fed-state simulated intestinal fluid.Liquid(FeSSIF) or human gastric or intestinal fluid (HIF).

While analyzing and characterizing the starting materials of the active pharmaceutical ingredient (API), we have also invested significant effort in understanding and optimizing the crystal structure, as well as identifying the potential pseudothermodynamic stable form of the substance. These studies are investigating the polymorphs, solvates, and salts formed by this material under various conditions to determine the most suitable material for formulation development, scale-up, and later-stage manufacturing.

Polymorphs appear in various structures, such as non-mixed polymorphs (free base or acid) or mixed polymorphs, such as salts, co-crystals (Vishweshwar et al., 2006), guest substances, hydrates, or solvates (Bernstein, 2002; Brittain, 1999).

Although polymorph screening in the past focused more on the number of different polymorphs crystallized in different solvents, it has now shifted towards qualitative data on polymorph formation under thermodynamic control conditions to obtain more accurate data on the potential risk of polymorphic changes in the final dosage form under expected storage conditions. These constant and controlled conditions include pressure, temperature, solvent, and time. Once polymorphs are identified and characterized, additional polymorph assessment experiments should be conducted to provide information on their kinetic stability.

The assessment must first determine, for example, whether the substance forms only one hydrate or several hydrates. Once the different polymorphs are identified, it is important to characterize whether they are enantiotropically or monotropically related. In the case of enantiotropic transitions, the transition temperature and temperature stability range must be well characterized. Long-term stability should be tested for at least two months in slurry experiments at temperatures within the stability range of the different non-solvates forming solvates and/or hydrates. From this series of polymorph screening experiments, the thermodynamically most stable form will be selected and further evaluated in competitive slurry experiments at room temperature against any other known anhydrous forms and solvates. The reversibility between different forms will be included in the evaluation of long-term slurry experiments and summarized using binary and ternary phase diagrams. For instance, seven modifications of formoterol fumarate were found during polymorph screening.

Through polymorph screening, the dihydrate form was identified as the most stable solid form because it facilitates the formation of effective hydrogen bonds between formoterol and fumarate, resulting in a well-packed crystal structure (Jarring et al., 2006).

In order to improve the physicochemical properties of drug substances in manufacturing, separation, and long-term storage, as well as to enhance the solubility and/or dissolution of active pharmaceutical ingredients (APIs),OutPerformance: Traditionally, medicinal chemists have preferred to use weak bases or weak acids to form salts. Since only 20-30% of new molecules readily form salts, 70-80% remain challenging (Serajuddin and Pudipeddi, 2002). Salt formation is a two-step process where proton transfer in solution must occur, followed by a crystallization step. Identification of suitable solvents is required to achieve sufficient attraction for the salt form and overcome ion and molecular solvation. To obtain thermodynamically stable salts with adequate water solubility, understanding specificCounterionThe salt structure formed is crucial. The counterion acts as a template, interacting with the molecule via non-covalent bonds through its conformation and bonding capabilities, directly influencing the three-dimensional structure. A database of possible salt structures based on functional groups can provide valuable predictions regarding the number of possible solvates and hydrates and their coordination numbers, where the coordination number is defined as the number of non-covalent bonds formed by the ion (e.g., Cambridge Crystallographic Data Centre). The selected salts of the molecule will be evaluated in the salt screening process according to the same principles as polymorph screening, to study their long-term stability, their conversion into other more stable salts, and their precipitation in various aqueous and biologically relevant media.

As understanding of the impact of polymorphs and salts in drug discovery grows, automated tools are being developed to standardize and implement these experiments as a routine part of drug discovery and lead compound selection (York, 1999; Rohl, 2003).

To overcome issues of poor water solubility or unstable bioavailability, chemical modification leading to prodrugs has been successfully applied to several substances. The most commonly used prodrug approach is the incorporation of polar or ionizable moieties into the molecule. The incorporation of N-acyloxyalkyl groups with varying chain lengths results in reduced lattice interactions and a decrease in melting point with an increase in the number of methylene groups (Stella et al., 1998). In vivo studies in dogs using N-acyloxyalkyl derivatives of phenytoin confirmed thatEatingUnder this condition, the bioavailability is higher and is not related to the decrease in water solubility (Stella et al., 1999). Prodrugs may also reduce precursor metabolism of substances in the gastrointestinal tract or the release of the drug itself by enzymatically cleaving the prodrug moiety near the site of drug absorption. Fosphenytoin, a phosphate prodrug of phenytoin, releases its active component phenytoin through phosphatase metabolism. In vivo studies in dogs and humans have shown better bioavailability after oral, intramuscular, and intravenous administration. Moreover, fosphenytoin demonstrates improved safety compared to the original form of sodium phenytoin (Stella, 1996). Successful examples of phosphate prodrugs include fosphenytoin (CerebyxTM) and fosamprenavir (VX-175/GW908). Another successful prodrug development is bortezomib, a boronic acid prodrug (VelcadeTM) (Sanchez-Serrano, 2006). Current research focuses on developing new prodrug moieties such as N-glycine, sulfinamide, and cysteamine to enhance bioavailability through improved solubility or metabolic stability.

Once determinedPilotThe most thermodynamically stable form of a substance, along with its solubility characterization, can provide essential information for predicting in vivo performance and designing drug delivery systems when studied through in vitro, computational, or animal in vivo experiments to evaluate its biopharmaceutical properties.

3. Biologics of Active Pharmaceutical IngredientsPharmaceuticsEvaluation

BiologyPharmaceuticsEvaluation and prediction are another key part of the main candidate drug selection process. Today, it is widely accepted that drugs that do not meet at least some biological criteriaPharmaceuticsStandard drug substances will be returned to the medicinal chemist forPilotOptimization (Clark and Grootenhuis, 2003).

One of the most critical aspects of in vitro screening assays is determining the true concentration of free drug in the assay. The concentration of free drug is often calculated rather than directly measured. It has been reported that, due to the dilution process (e.g., from buffered aqueous solutions or DMSO solutions), the drug'sMediumThe solubility and precipitation in the solution were unexpectedly low. When the calculated drug concentration in the assay is not reached, erroneous conclusions regarding efficacy, toxicity, or permeability are most likely to be drawn (Di and Kerns, 2004).

Table 3 lists the main in vitro tools used to evaluate drug absorption and permeability.

CaCo-2 cell monolayers are a well-established in vitro system used at various stages of the drug development process to assess drug absorption and underlying processes (Shah et al., 2006). The CaCo-2 cell line provides valuable information regarding drug permeability and absorption potential. Later in development, they can also be used to provide insights into the potential impact of metabolic or efflux systems on the active pharmaceutical ingredient and to classify drugs according to the BCS.

When using CaCo-2 cell monolayers to measure the permeability of poorly soluble substances, attention must be paid to possible drug accumulation within cells, binding to proteins, or adherence to plastic surfaces. To avoid variations in permeability data obtained through CaCo-2 assays exceeding ±10%, standardization and calibration are crucial.

Parallel Artificial Membrane Permeability Assay (PAMPA) is an artificial intrinsic permeability measurement method used for drug lead selection and high-throughput preclinical research. The PAMPA system is based on synthetic phospholipids and fatty acids that simulate physiological conditions. PAMPA is used as a low-cost alternative to cell-based systems for early ADME screening (Avdeef, 2005). It has been reported that PAMPA shows good effective permeability (>10^-6 cm/s) and poor effective permeability (<2.5^-6cm/s) is high, while the results for drugs in between are difficult to interpret.

To study drug absorption mechanisms efficiently and rapidly, the CaCo-2 cell monolayer was combined with the PAMPA assay (Kerns et al., 2004). The drugs of interest in the comparison are mainly absorbed through passive diffusion. Substances in PAMPA exhibit higher permeability than those in the CaCo-2 model and are substrates for acid efflux or exhibit reduced passive diffusion under the CaCo-2 pH gradient. Compared to the PAMPA system, substances with higher CaCo-2 cell permeability suggest potential absorption mechanisms such as paracellular or active transport.TransferOr in CaCo-2CellIncreased passive diffusion in the pH gradient.

Immobilized Artificial Membrane (IAM) is a solid-phase model of liposomal membranes used in studies to partition drugs into the membrane. IAM chromatography is a simple experimental tool that allows for high-throughput screening tests during the drug discovery phase to determine the potential for drug absorption, independent of other factors contributing to poor bioavailability, such as systemic pre-metabolism, efflux systems, or transport proteins (Pidgeon et al., 1995).

Prediction of drug absorption in the colon remains poor. The contribution to drug absorption is still unclear due to paracellular or carrier-mediated uptake, reduced efflux mechanisms, decreased surface area, the colonic dissolution environment (pH 6-7), reduced volume and mixing, and unknown chemical metabolism of substances along the gastrointestinal tract. However, poorly soluble substances and drugs in sustained-release formulations may reach the colon at relatively high concentrations and remain there for an extended period. Even with slow absorption, this could significantly enhance absolute bioavailability.

One of the earliest predictive models used mathematical methods to estimate the absorbed dose fraction (Oh et al., 1993). This mathematical calculation uses only four parameters to estimate the absorbable dose: initial saturation, absorption number, dose number, and dissolution number.

For predicting drug absorption in humans today, the Specific Absorption Rate (SAR) or the Human Absorbable Dose (Dabs) model is often used. SAR plots the relationship between absorption numbers and dose numbers (Collins and Rose, 2004). The Dabs model is based on the permeability of the substance, its solubility in simulated intestinal fluid, and is defined as 800 cm.²The human gastrointestinal tract has a surface area and a gastrointestinal transit time of 3.3 hours (Yu, 1999). Plotting Dabs against the expected therapeutic dose has implied whether drug absorption is the rate-limiting step for conventional dosage forms. For example, pioglitazone, a weak base with good solubility at low pH, does not require formulation enhancement due to its solubilization in the stomach; the same applies to tadalafil, which is a non-ionizable substance within the physiological pH range and has low solubility in all relevant media due to its low dose (20mg).

Another proposed model is to use the concept of Maximum Absorbable Dose (MAD), taking into account the 4.5-hour small intestine transit time, 250ml of small intestinal fluid volume, drug solubility, and absorption constant (Johnson and Swindell, 1996). If the predicted human dose can be absorbed, the MAD value provides a good prediction. Evaluating a series of substances, it can serve as a guiding tool for potential lead drugs within a specific series of substances.Candidate ChemicalsPerform sorting (Curatolo, 1998).

Starting with the MAD model, a computational system was developed to simulate drug absorption in vivo (Johnson, 2003). Other input parameters were introduced, such as the water absorption rate of the gastrointestinal tract and variations in gastrointestinal permeability, to improve the simulation. Another computational system for simulating drug absorption is based on the Advanced Compartmental Absorption and Transit (ACAT) model (Agoram et al., 2001). The ACAT model is an extended version of the Compartmental Absorption and Transit (CAT) model, which uses seven small intestine compartments for prediction. The ACAT model treats the colon as another compartment for drug absorption, which cannot be ignored for poorly soluble and poorly permeable substances as well as for sustained-release formulations. Each compartment...OutThe choice of medium is an important factor affecting the prediction accuracy of the ACAT model. For example, at pH 6.5, FaSSIF is used.MediumBetter correlation for soluble substances is provided than simple buffer systems. However, for poorly soluble substances, the pH 6.5 buffer is more likely to be below the predicted value, while the FaSSIF medium may be above the predicted value. The output of the ACAT model has been improved by including other parameters of the active pharmaceutical ingredient such as particle size/radius, density, diffusion coefficient, logD, pKa, and molecular weight. The simulations of both systems are relatively good, but due to the difficulty in simulating colon drug absorption, the simulation for poorly soluble substances tends to be less accurate.

Currently, the main limitations of computer simulation models lie in potential drug precipitation in the gastrointestinal tract (e.g., salts of weak bases and poorly soluble substances), the impact on colonic drug absorption, especially for poorly soluble drugs at high doses, and the influence of drug particle size on absorption. Although further validation work is ongoing, existing computer-aided tools have already provided insights for potential candidates.CompoundThe selection and/or optimization provides important information and can be further developed to improve the accuracy of the simulation (Kuentz et al., 2006).

In the solubility/dissolution of substances in aqueous or biologically relevant mediaOutBehavioral BiologyPharmaceuticsAfter evaluation, its permeability, chemical and metabolic stability are assessed in vitro. Subsequently, the absorption, food effect, first-pass metabolism, and PK profile are quantified in different animal species (rats, dogs, monkeys) through dose escalation. These studies aim to establish the initial in vivo oral exposure rate and dose linearity. For these studies, the drug is administered in solid, suspension, or solution form. These studies should also provide information on any dependence of absorption on particle size, as well as the exposure ceiling, clearance, and potential food effects of standard formulations.

Later, especially when considering the potential for the development of sustained-release formulations, more in-depth studies on drug absorption mechanisms can be conducted using, for example, regional perfusion models applicable to animals (such as dogs) or humans (Lenneras et al., 1992). Regional perfusion models are also used to establish correlations between human permeability and CaCo-2 cell permeability (Lenneras et al., 1997), providing important information for the design of drug delivery systems. To facilitate and improve research on regional drug absorption and its underlying mechanisms, special capsules have been developed that allow time- and site-controlled release of drugs or formulations in specific regions of the gastrointestinal tract (Wilding et al., 2000). In order to obtain at least some data on human drug performance before selecting lead compounds or entering clinical development, the European Medicines Agency (EMEA) has recently accepted the concept of single microdose studies in humans (EMEA, 2003). Microdosing studies allow a single dose to be less than 1/100 of the calculated pharmacological dose, with a total small molecule dose not exceeding 100.μgNevertheless, to date, the experience with microdosing studies and their value in the drug development process remain very limited. Microdosing holds promise as a useful tool for identifying substances with key biopharmaceutical properties and significantly improving computer predictions of drug absorption and deposition (Wilding and Bell, 2005).

Although some tools provide highly valuable data for the selection of potential candidates for one substance, they may not offer data for other substances. Therefore, a range of different in vitro, in vivo, and predictive methods and tools provide a solid foundation for developing meaningful evaluation plans, which must be designed for each substance based on the information gathered during the drug discovery and substance characterization processes.

4.Candidate DrugSelection

Multidisciplinary teams are becoming the main candidates in the pharmaceutical industryCompoundAn important part of the selection process. Their goal is to select from chemistry as well as pharmacology, toxicology, and biology.PharmaceuticsFrom the perspective of resolving various characteristics of active pharmaceutical ingredients (APIs) as early as possible. These multidisciplinary teams collectively assess the substance's ability to become an effective and safe drug through various criteria (Bowker002). While receptor affinity in high-throughput screening remains the baseline for selection, greater attention is now being paid to the characteristics themselves, as they may determine potential issues during the development process (Table 4).

The lead selection process can be part of the development process at various stages between drug discovery and clinical development. The aforementioned tools can essentially be utilized at different stages of the drug discovery and lead optimization processes, and their accuracy, precision, and predictability will gradually improve as knowledge about substances accumulates. During the discovery phase, a large number of substances are evaluated, and rough estimations based on MAD, molecular physical parameters (such as the "Rule of Five" (Lipinski et al., 1997)), and permeability data of structurally related substances may trigger alerts and provide guidance to steer clear of structural areas known to cause absorption issues. Once a series of substances have been synthesized, pharmacokinetic screening should be conducted in animals and CaCo-2 cells. At least for some of the synthesized substances, this screening along with solubility testing can provide...PilotThe optimization plan provides further guidance. When selecting some substances as potential lead candidates, at least two types of animal metabolism and pharmacokinetic studies, as well as further solubility studies, should be conducted. Considering the anticipated human dose, these data will provide better outputs in predictive tools such as MAD and computer models (Curatolo, 1998).

The decision-making process for entering clinical projects includes a rigorous review of the tests conducted and the consistency of the data derived from these experiments, which may reveal issues caused by substance solubility characteristics. Substances with insufficient water solubility, particularly when expected to be administered at high doses, may not display their toxicological profiles because they fail to reach the calculated concentrations in toxicology studies.

If a substance forms a stable and poorly soluble form (such as a salt) with physiological fluids or food components, the potential risk of drug precipitation in the gastrointestinal tract needs to be considered. Physical properties must also be addressed from a processing perspective. During large-scale commercial synthesis and manufacturing processes, the hygroscopicity, amorphousness, crystallinity, and polymorphism of the substance need to be controlled and managed within an industrial setting. For solubility...OutFor substances with limited solubility or absorption, variations in bioavailability are often observed, which may be a critical selection criterion. This variability may be perceived as a food effect, but it could also only manifest in specific patient populations (elderly, pediatric) or disease stages. In such cases, strategies to minimize inter- and intra-subject variability must be considered as early as possible.

InPilotIn the process of identification and optimization, the pharmacology and biology of the API must be considered.PharmaceuticsAll qualified data of the characteristics. MainlyCandidate ChemicalsThe selection is a complex decision-making process involving all disciplines. The selection process does not necessarily lead to the choice of one.PilotMaterial; it can also be further optimizedPilotProvide clear directions and recommendations on substances.

Although there is usually discussion aboutPilotA large amount of data on substances, but for possible alternative substances or potential optimizationsPilotIn terms of substances, these data do not necessarily exist. The lack of these data makes it difficult in major...Candidate ChemicalsIt is difficult to decide whether to stop using the main substance or modify the molecule during the selection process, whether introducing additional functional groups at this stage or "reducing" the molecule. The decision-making process will include evaluatingPilotWhether the expected limitations of the substance can be addressed through specific technologies or commercially viable pharmaceuticalsDeliveryStrategically easy to solve, or whether it can be successfully developed within the timeline of bringing the substance to market as a commercial product.

5. Formulation Strategies for Solubility and Bioenhancement

Initial drug discovery screens are often conducted using amorphous forms of the substance in dimethyl sulfoxide (DMSO). These high-energy forms of the "formulation" are sufficient for receptor and efficacy screening but overlook any solubility characteristics of the substance at this stage, thus precluding relevant biopharmaceutical (i.e., absorption) assessment.

To continue early drug discovery programs, sufficient concentrations of amorphous or crystalline drugs dissolved in aqueous test media are required for appropriate in vitro and in vivo testing. When the solubility of a substance in an aqueous medium is limited, formulation strategies need to be developed early in the drug discovery process; these strategies remain critical for lead compound selection and commercial drug development. Table 5 summarizes the main drug solubilization strategies.

To support early drug discovery initiatives, experimental formulations were developed and studied for solubility.OutAnd short-term stability. When the substance'sSolubilityOr SolubleOutWhen identified as an issue in both in vitro and in vivo testing, apply a simple and effective formulation strategy to ensure the desired drug deposition in both in vitro and in vivo trials.

Reducing particle size is one of the earliest studied strategies. Wet milling is used to reduce particle size, achieving approximately 200nm. If this does not result in the desired concentration in in vitro tests or in vivo exposure, formulations containing solubilizers (such as cyclodextrins or micellar systems) are evaluated. Other systems used are solvent- and surfactant-based formulations (e.g., microemulsions) or solid dispersions. The latter system requires significant development time and may be limited due to potential excipient-related toxicity or adverse effects on the test system.

The solubilization efficiency of low molecular weight polyethylene glycol (PEG) is often used for drug solubilization in in vivo studies. In addition to its solubilization effect, low molecular weight PEG, such as PEG400, has been shown to have a dose-dependent impact on drug absorption. Depending on the amount of PEG400 in the formulation, the absorption of ranitidine increases (1gPEG increased by 41%) or decreased (2.5 and 5.0g PEG decreased by 38%). Although gastric emptying remained unchanged, PEG increased intestinal transit time (1, 2.5, and 5.0 grams increased by 9%, 20%, and 23%, respectively). The increased absorption of 1g PEG400 may also indicate the effect of PEG400 on intestinal permeability (Schulze et al., 2003).

As mentioned above, the solubility of a substance depends on its solid-state form. To obtain the most soluble form of a drug, a recently developed technique allows for the preparation of sufficiently stable amorphous nanosuspensions with particle sizes in the 100nm range. The drug is dissolved in an organic water-miscible solvent. The active pharmaceutical ingredient (API) organic solution is then added to an aqueous solution containing stabilizers and mixed using ultrasonication. The amorphous form of the drug is generated through a homogeneous nucleation process, which precipitates into the aqueous phase, removing the organic solvent from the aqueous phase. To prevent particle growth caused by Ostwald ripening, poorly water-soluble stabilizers (mainly non-ionic polymers such as PVP or HPMC) are incorporated into the aqueous phase when adding the organic drug solution. The stabilizer acts as an Ostwald ripening inhibitor and prevents particle growth during storage. For felodipine, nifedipine, and bicalutamide, a Miglyol ratio of drug/inhibitor at 4:1 is sufficient to prevent Ostwald ripening, while additional components are required for other studied drugs. In this case, decanol is added as an extra, essentially water-insoluble component in a 1:1 ratio with Miglyol, and the combination ratio of drug to inhibitor is 4:1, successfully inhibiting particle growth. When forming a homogeneous mixture with the amorphous drug, the inhibitor or combination of inhibitors prevents Ostwald ripening (Lindfors et al., 2006a).

Solubility of Amorphous MaterialsOutIt can be determined using light scattering techniques in nano-suspensions. The basic principle of light scattering technology is to determine the appearance of colloidal particles as the concentration increases. It has been found that the dissolution amount of amorphous nano-suspensions is several times that of the corresponding crystalline form. The difference in solubility between amorphous and crystalline forms can be calculated from the chemical potential difference using solubility and thermodynamic data at the crystal melting point (Lindfors et al., 2006b).）

Amorphous nanosuspensions can be routinely used as experimental formulations in the early drug discovery phase.

Recently, nanodispersions of amorphous drug materials have been prepared using sugar glass. Sugar glass is a physically stable amorphous system (in the glassy state) with high water solubility. Methods for preparing nanodispersions using trehalose, sucrose, and two different inulins (inulin DP21 and DP23 with degrees of polymerization of 21 and 23, respectively) as sugar glass carriers have been described. Amorphous nanodispersions of diazepam were prepared by dissolving sugars in water and dissolving the drug in tert-butanol. The two phases were mixed at a water∶alcohol ratio of 6:4, followed by freeze-drying. Diazepam was incorporated in an amorphous form, reaching concentrations of up to 100% at drug loads of 10% and 20% across all sugars, up to 97% at drug loads of 40% in trehalose and 63% in inulin DP21 and DP23, while the amorphous form accounted for only 89% in sucrose. After being stored for 60 days at 25°C and 45% relative humidity, no increase in crystal size of diazepam was observed in the nanodispersions of inulin DP21 and DP23 at drug loads up to 20%, whereas significant crystallization progressed in other sugars. Crystallization was also observed at a drug load of 40% for inulin DP21 and 63% for inulin DP23. This difference is attributed to the high glass transition temperature of inulin, which favors the physical stability of the nanodispersions (VanDrooge et al., 2004a). Solubility of various amorphous sugar glasses.OutBehavior depends on the dissolution of sugar glass.OutAnd the concentration of the incorporated drug. In rapidly dissolving sugars (trehalose and sucrose), the initial release was fast but was then counteracted by crystallization induced by supersaturation in the boundary layer on the tablet surface. For slower-dissolving sugars (inulin DP21 and inulin DP23), this phenomenon was less pronounced. Crystallization was also found to be related to the drug load in the sugar. When amorphous drugs dissolve,OutCurve and Carrier SolubilityOutWhen the curves align, optimal dissolution is achieved.Out(VanDrooge et al., 2004b). Further research is being conducted to enhance the solubility of poorly soluble substances in sugar glass, including the addition of surfactants and controlled crystallization, to obtain sugar glass containing nanocrystalline drugs.

Cyclodextrins (CD) are cyclic oligomers typically composed of 6-8 glucose units. CD represents a class of solubilizers that form non-covalent, dynamic complexes with lipophilic molecules through inclusion. The inclusion complex temporarily alters the physical properties of the substance. Controlled by the equilibrium constant between free drug, free CD, and drug-CD complexes, the drug is continuously and rapidly released upon dilution. CD has been shown to enhance the stability of substances such as proteins or peptides (Davis and Brewster, 2004). CDs approved for pharmaceutical use can be divided into three main types, differing only in molecular weight and respective central cavity diameter. The molecular weight of α-cyclodextrin (-CD) is 972, with a central cavity diameter of approximately 5A.β-The molecular weights of CD increase to 1135 and the central cavity diameter is approximatelyFor6.2A，γ-The molecular weight of CD increased to 1297 and the central cavity diameter is approximatelyFor8A. Although most oral CD products on the market use -CD complexes, -CD has some limitations due to its poor water solubility, possible formation of crystalline complexes, and nephrotoxicity when administered parenterally. To improve the properties of cyclodextrins, chemical modifications have produced two new derivatives: 2-hydroxypropyl cyclodextrin (HP-CD) and sulfobutylether cyclodextrin (SBE-CD). HP-CD is an amorphous mixture of isomers that maintains its complexation potential while exhibiting improved water solubility. Using itraconazole as a model substance, the complexation behavior of HP-CD was studied. It was found that the complexation of itraconazole with HP-CD depends on the CD/drug ratio and the system's pH (Peeters et al., 2002). The safety of HP-CD was thoroughly investigated, revealing good tolerance both orally and via injection, with limited toxicity. After intravenous administration of HP-CD, the elimination half-life is short, less than 2 hours, following dose-proportional kinetics. Orally, less than 3% of HP-CD is absorbed (Gould and Scott, 2005). HP-CD has been monographed in the European Pharmacopoeia, and both HP-CD and SBE-CD are listed on the FDA’s Inactive Ingredients List. Parenteral and oral formulations have been approved and marketed in the United States and Europe.

Lipid-based drug delivery systems represent a variety of formulations composed of lipophilic, amphiphilic, and hydrophilic excipients that are capable of dissolving drugs with poor water solubility and lipophilicity. The system is specifically designed for each drug to exhibit other characteristics, such as self-emulsification, upon exposure to an aqueous medium. Lipid-based drug delivery systems have been shown to enhance oral bioavailability, reduce food effects, and deliver lipophilic drugs to the lymphatic system (Charman, 2000).

In the past few years, there has been significant progress in understanding lipid-based formulations to better design and evaluate these systems for drug delivery of poorly soluble substances. It has been recognized that orally administered lipid formulations undergo physiological digestion and their system characteristics can be significantly altered before reaching the absorption site.

Lipid digestion begins with the secretion of lipases and co-lipases by the salivary glands, gastric mucosa, and pancreas, which hydrolyze triglycerides into diglycerides, monoglycerides, and free fatty acids. After the release of bile salts, vesicles and colloidal particles are formed and released from the lipid surface. As they travel along the gastrointestinal tract, they further dissolve into a series of emulsion droplets, vesicular structures, and mixed micelles containing bile salts, phospholipids, and cholesterol (Porter and Charman, 2001). Each of these micellar and vesicular structures represents different solubilization capacities for active pharmaceutical ingredients and may directly impact drug deposition. In vitro digestion models have been developed to evaluate formulation digestion and its effect on drug solubilization (Kaukonen et al., 2004a, b). The solubilization capacity of lipid formulations for drugs may be affected by digestion, thereby influencing bioavailability. Lipid formulations of danazol, which has low water solubility, were prepared as simple solutions of long-chain triglycerides and two self-emulsifying systems composed of long-chain lipids (C18) and medium-chain lipids (C8-C10). After in vitro digestion, precipitation of danazol occurred in the medium-chain-derived self-emulsifying system, resulting in a five-fold lower bioavailability (AUC) in dogs compared to the long-chain self-emulsifying system. The study also showed that two different formulations (long-chain triglyceride solution and long-chain-based self-emulsifying system) exhibited similar bioavailability, which can be explained by digestion leading to similar absorption phases in vivo (Porter et al., 2004).

Highly lipophilic substances with low water solubility (logP>5) may be suitable candidates for absorption via the lymphatic pathway. After digestion, short- and medium-chain triglycerides and fatty acids are directly absorbed into the portal vein, whereas long-chain triglycerides and long-chain fatty acids lead to the formation of chylomicrons, triggering lymphatic absorption. For effective drug delivery to the lymphatic system, the minimum solubility of the drug in long-chain triglycerides should be 50 mg/ml to ensure sufficient dissolution within chylomicrons (Porter and Charman, 2001). Lymphatic absorption results from smaller animals (e.g., rats) were found to underestimate the potential transport capacity in humans. To better predict lymphatic absorption in humans, a triple-cannulated dog model was developed to collect thoracic lymph, portal vein, and systemic blood samples, assessing the lymphatic absorption of formulated drugs under both pre- and post-prandial states (Khoo et al., 2001).

Lufangchun free base is a highly lipophilic substance (calculatedLogP≈8.5; solubility in triglycerides ≈50mg/ml). Halogenated alkanols are primarily absorbed through lymphatic transport, with absorption increasing after food intake. When simulated as microemulsions containing long-chain or medium-chain lipids under fasting conditions, it can be demonstrated that even formulations with small lipid volumes can stimulate endogenous triglyceride release, lipoprotein formation, and drug transport via the lymphatic pathway (Khoo et al., 2003).

A similar effect was observed when using poorly lipid-soluble halogenated aromatic alcohol hydrochlorides. These studies indicate that under fed conditions, the intestinal solubilization of halogenated arylalkanol HCl leads to its conversion into the lipophilic halogenated aryl alcohol free base, which is then incorporated into chylomicrons formed during the lipid digestion process (Khoo et al., 2002; Taillardat-Bertschinger et al., 2003).

For lipid-based formulation systems, particular emphasis is placed on self-emulsifying drug delivery systems (SE) (Constantinides, 1995). SE typically consists of 3-5 excipients in a specific ratio, forming thermodynamically stable microemulsions upon exposure to water. When the particle size is less than 200nm in water, the system appears semi-transparent. SE can be designed through rational selection and combination methods of excipients. The starting point is selecting substances for SE, which need to meet certain criteria regarding dosage, permeability, and logP (Benameur, 2006). The solubility of these substances in different lipophilic, amphiphilic, and hydrophilic excipients was studied. Phase diagrams of excipient mixtures were plotted, with excipients usually consisting of combinations of lipophilic solvents (oil), hydrophilic solvents (water), surfactants, and active pharmaceutical ingredients. Further evaluation was conducted on the phase behavior and thermodynamic stability of excipient combinations that form microemulsions with the active pharmaceutical ingredient (Kang et al., 2004).

The selected lead formulations will be characterized based on their isotropy, rheological behavior, thermodynamic and physical stability, and droplet size in aqueous media. CaCo-2 cells can be used to compare the permeability of pure drugs with formulated drugs to select the lead SE formulation. Published data (Gao et al., 2004; Kang et al., 2004) and unpublished data from several case studies confirm that for drugs whose bioavailability is limited by solubility in aqueous media, a rational approach to designing SE systems can enhance the in vivo absorption of the drug.

Recent findings suggest that insoluble substances are mainly bound in the mantle close to the core.（mantle）In, rather than in the lipophilic core of emulsion droplets, this has drawn more attention to the surfactants themselves. Their hydrophobic chains and hydrophilic head groups mainly determine the solubilization capacity of existing non-ionic surfactants. To enhance the solubilization capacity, new non-ionic surfactants were designed by modifying the hydrophobic chains and hydrophilic head groups. Compared with existing non-ionic surfactants (polyoxyethylene ether derivatives), N,N-dimethylalkylamine-N-oxides (DDNO) showed improved solubilization capacity for most poorly soluble substances (betamethasone, cortisone acetate, testosterone, phenylbutazone, griseofulvin). Since the toxicity profile of DDNO is mainly attributed to its metabolic stability, a biodegradable version of DDNO was synthesized by introducing a biodegradable carbonyl linker. The solubilization capacity of N,N-dimethyl-N-(3-dodecylcarbonyloxypropyl) amine oxide (DDCPNO) was then studied. DDCPNO exhibited greater solubilization capacity than polyoxyethylene ether surfactants but lower than DDNO (Tolle et al., 2000). In further studies using another derivative of amine-N-oxide surfactants, N,N-dimethyldodecylamine-N-oxide (DDAO), it was found that the chain length of lipids in the oil phase and their ratio to DDAO influenced droplet radius and aggregation number (Warisnoicharoen et al., 2000). Therefore, solubilization in microemulsions depends on the nature of the oil and its incorporation into the microemulsion system, while in micellar structures, the head group is the most important.

Carotenoids represent a group of lipophilic compounds with critical bioavailability. Lycopene, an insoluble carotenoid derivative, has low bioavailability in its natural sources (such as fresh tomatoes), and the food industry has conducted research to enhance its bioavailability. Although reducing the particle size of lycopene crystals slightly improves bioavailability, processing (e.g., tomato paste) increases it three to four times. Studies on oral bioavailability have revealed the potential influence of the stereochemistry of lycopene molecules. In natural sources, the all-trans isomer is the predominant form (95%), which contrasts sharply with the in vivo stereochemical forms found in allicins. In the skin and prostate, the cis-isomers account for 70% and 85%, respectively. In vitro tests using micelles, chylomicrons, and CaCo-2 cells indicate that 30% of all-trans lycopene isomerizes to the cis form. Subsequent studies have demonstrated that processing influences the formation of cis-isomers, which may explain the higher bioavailability of processed natural sources (e.g., tomato paste). The findings suggest that stereochemistry may play a crucial role in lycopene absorption, with the 5-cis lycopene being the most favorable form for absorption.

To enhance the bioavailability of lycopene through formulation, lycopene was complexed with whey protein (lycopene emulsion) and spray-dried into powder form. The lycopene emulsion complex demonstrated bioequivalence with processed natural sources (tomato paste) and exhibited identical distribution in oral mucosal cells (Richelle et al., 2002).

When taken together with free or esterified plant sterols, the absorption of carotenes is reduced. While stanol esters have a specific impact on carotene absorption, these findings clearly highlight the importance of food components in drug absorption (Richelle et al., 2004).

6. Biologics of Drug Delivery SystemsPharmaceuticsEvaluation

When solubility is identified as a critical parameter for bioavailability and/or lead candidate selection, it is necessary to evaluate and compare the performance of formulation strategies in humans. Table 6 lists the methods used to compare different formulations or drug delivery systems with substances in terms of bioavailability.PharmaceuticsThe Main Tool for Evaluation.

The starting point for formulating strategies remains the solution.OutTest. Dissolution test methods may achieve different objectives, such as the selection of lead formulations, quality assessment of formulation reproducibility, establishment of in vitro/in vivo correlation (IVIVC), and regulatory purposes.

For substances with poor water solubility where dissolution rate is the main limiting factor for drug absorption (BCS Class 2), in vitro dissolution reflecting in vivo conditionsOutThe medium is crucial for the rapid screening and evaluation of formulations. Several solvents have been proposed and evaluated.OutMedia, such as FeSSIF, FaSSIF, SIF, etc., but their predictive accuracy is still insufficient. One of the main reasons is the complexity of gastrointestinal physiology and the digestive process, which remains unclear.

To investigate the luminal composition of the upper gastrointestinal tract in fasting and fed states, healthy volunteers received 250ml of water (fasting) or 500mlEnsurePlus® (Feeding), and samples were aspirated from the antrum and duodenum at different time points. EnsurePlus was selected.^®This is because it reflects the standard FDA meal used in bioavailability/bioequivalence studies. The results clearly show that, apart from the known variations in pH and bile salt levels under fasting and fed conditions, there are also differences in buffer capacity, surface tension, osmotic pressure, pepsin levels, and food composition (Kalantzi et al., 2006a).

These differences have not yet been dissolvedOutIt is well reflected in the medium, especially for the federal government. For example, in standard solventsOutAt the same pH level of the medium, significantly higher solubility of ketoconazole and dipyridamole was observed in the intestine (Kalantzi et al., 2006b). This was also confirmed by a previous study that characterized human intestinal fluid (HIF) in fasting and fed (FDA standard breakfast) subjects using a Loc-I-Gut perfusion tube. The solubility of several poorly soluble substances (danazol, felodipine, cyclosporine, and griseofulvin) was examined.OutIt was confirmed that, compared with fasting HIF or FeSSIF,EatingThe solubility of HIF is 3.5-30 times higher. This increase is mainly due toEatingUnder the condition of HIF, the bile salt concentration is 4 times higher and the phospholipid concentration is 14 times higher (Persson et al., 2005). In another study, the effect of gastric hydrodynamics on the bioavailability in dogs was investigated using felodipine solution, micronized powder (median particle size 8μm), and coarse suspension (median particle size 125μm).

Compared with the coarse suspension, the tmax of the micronized suspension was 22 times higher and the AUC was 14 times higher, and it was not affected by food intake, which is consistent withEatingThe AUC doubled in the state of coarse suspension, which is different. For felodipine, which has poor water solubility, when sufficient solubility is achieved through micronization, the mode of motion has little or no effect on bioavailability (Scholz et al., 2002).

Recently, a multi-compartment dynamic computer-controlled system used in the nutrition industry for evaluating and predicting the absorption and metabolism of functional food ingredients has been applied to drug absorption and dosage form evaluation. The system simulates the gastrointestinal tract through six small intestine compartments (TIM1) and two large intestine compartments (TIM2). Each compartment is designed to represent physiological conditions, including body temperature, peristalsis, gastrointestinal pH, gastrointestinal mixing and transit time, gastric acid and enzyme secretion, bile salts, pancreatic fluid, and the absorption of digestion products via an artificial membrane. The artificial membrane consists of Cuprophan dialysis membranes, which allow gradient-driven absorption processes and simulate sink conditions. The dialysis membrane only reflects absorption through passive diffusion and does not permit active transport mechanisms. The system aims to evaluate the in vivo performance of active pharmaceutical ingredients or drug delivery systems under fed and fasted conditions. It provides critical information on the potential risks of food effects, drug precipitation, and even drug-drug interactions. Overall, using acetaminophen as a model drug, the system has demonstrated good reproducibility and correlation with in vivo human studies (Blanquet et al., 2004). The main drawbacks are limited throughput (only one study per day), lack of automation, variable recovery of poorly soluble substances, and limited absorption. Although this hinders the system from being widely used as a screening tool in development today, it is expected that the system will be further developed before first-in-human studies to enhance its performance in formulation screening.

Magnetic Marker Monitoring (MMM), also known as magnetic moment imaging or gastrointestinal magnet labeling, has been introduced as a very interesting tool for the continuous monitoring of dosage form fate through the gastrointestinal tract via non-invasive means (Weitschies et al., 2001). An erosion-controlled sustained-release felodipine tablet was developed, and its gastrointestinal position and erosion status were monitored under fasting and fed conditions. The results confirmed that...EatingUnder conditions, the position of the tablet and plasma concentration vary among subjects. However, plasma concentration is mainly influenced by the position of the tablet in the gastrointestinal tract. The dose dumping observed under fed conditions is directly related to the residence time of the formulation in the proximal stomach. Under fasting conditions, early gastric emptying has been identified as the reason for the correlation between plasma concentration and tablet release (Weitschies et al., 2005). Regulatory authorities have developed guidelines for establishing in vitro-in vivo correlation (IVIVC) of pharmaceuticals (USP29/NF24; FDA Guidance, 1997, 2000; EMEA, 2000). Due to the difficulty of easily translating the theoretical concept of IVIVC into practical applications, its use has been narrowed to extended-release products, quality assurance purposes, and essentially similar products. With the introduction of BCS, Class II substances have also been identified as another category for which IVIVC should be established. The limitation of using IVIVC as a substitute for bio-studies is the lack of biorelevant dissolution media. Dissolution data in biorelevant media, combined with computer simulation methods, may help predict IVIVC simulations and assist in regulatory decision-making for product changes and approvals.

7. Future Outlook

In the past few years, there has been an increasing understanding of the solid-state properties of drug molecules, with efforts to evaluate and modify them to achieve greater stability and better solubility.OutFeatures, creating a series of new technologies. Their further development and routine application have already improved and will continue to improve the selection process for candidate drugs.

Understanding physiological fluids under fasting and fed conditions will facilitate biologically relevant solutions.ExitThe development and quality of the medium. The simultaneous application of plasma levels and MMM will further enhance the understanding of the performance of drug delivery systems. The use of biorelevant media can predict the plasma profile of lipophilic drugs with known absolute bioavailability (Nicolaides et al., 2001), which will become an integral part of the selection process for lead candidates and primary formulations, potentially replacing many in vivo studies.

Based on this understanding, drug delivery technology can be optimized.

In selecting lead candidates or developing suitable drug delivery systems, increasing consideration is given to the complexity of gastrointestinal physiology and the drug absorption process. Drug delivery strategies are often developed based on comprehensive approaches to underlying physiological processes, such as the binding and transport of lipids through fatty acid binding proteins (FABP) in enterocytes (Velkov et al., 2005), and the lymphatic lipid precursor pool (LLPP) for lymphatic absorption (Trevaskis et al., 2005, 2006a, b).

It has been recognized that colonic absorption may be mainly attributed to the absorption of insoluble substances and sustained-release preparations. A further understanding of the role and involvement of the colon in drug absorption will help better predict insoluble substances and develop new drug delivery strategies.

In addition, more interdisciplinary work is underway to improve drug discovery and lead compounds.Candidate ChemicalsSelection and drug development. Neither medicinal chemistry nor pharmaceutical sciences alone can address the challenge of developing safe and effective therapies for unmet needs.

8. Summary

Understanding the Different Root Causes of Poor or Highly Variable Oral Bioavailability of Drugs Has Been a Key Asset in Finding Solutions. It is well-known that limited solubility of drugs under gastrointestinal physiological conditions is one of the main root causes. New tools and technologies have been developed and introduced into pharmaceutical development as part of the primary candidate drug selection process, which has largely addressed the solubility factor at an early stage. Continuous scientific advancements have also made us aware of the complexity involved in identifying and developing innovative therapies for unmet medical needs. Interdisciplinary approaches from medicinal chemistry and pharmaceutical sciences in both academia and industry have been widely practiced. This has led to, and will further lead to, significant progress in bringing new innovative products to market, but due to the poor profile of today's industrial clinical product pipelines, community perception will lag behind.

The materials science team is closely monitoring the active pharmaceutical ingredients and their most suitable forms for development in terms of stability and solubility. Early assessments are conducted, followed by experimental formulation work to ensure the solubilized drug concentration in preclinical trials. The development process is supported by various computational tools that can roughly predict possible crystal forms of the drug and its in vivo performance. When bioavailability issues are identified, formulation strategies for clinical and commercial stages are studied early on. Formulation approaches to enhance solubility have been developed and continue to evolve. More complex efforts are underway to better understand gastrointestinal physiological conditions and the underlying processes of drug absorption, which will lead to improved in vitro evaluation and prediction tools, as well as more targeted drug delivery systems.

Review of the Series on Perspectives from International Pharmaceutical Giants:

Review Series on Solubilization Strategies for Poorly Soluble Drugs:

Formulation Process Development: