Potential Of Solubility In Drug Discovery And Development

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Solubility of active pharmaceutical ingredients (API) has always been a concern for formulators, since inadequate aqueous solubility may hamper development of parenteral products and limit bioavailability of oral products.

In recent years, the problem has become more acute and more common as pharmaceutical companies cast the drug discovery net ever wider in the anticipation of finding new therapeutic approaches and improving drugs for existing therapeutic areas. Experimental determination of drug solubility is not a single event but is performed multiple times along the drug discovery and development process, the assays and their focus varying with the phase. Among the five key physicochemical screens in early compound screening, pKa, solubility, permeability, stability and lipophilicity, poor solubility tops of the list of undesirable compound properties. Compounds with insufficient solubility carry a higher risk of failure during discovery and development since insufficient solubility may compromise other property assays, mask additional undesirable properties, influence both pharmacokinetic and pharmacodynamic properties of the compound, and finally may affect the developability of the compound. Ideally solubility liabilities should be known prior to any functional evaluations.


Conceptually, solubility is an easy parameter to measure but its meaning and concept of use is often different for discovery and development scientists and this can be a source of misunderstandings and controversy. In a broad sense, solubility may be defined as the amount of a substance that dissolves in a given volume of solvent at a specified temperature. More specifically, compound solubility can be defined as unbuffered, buffered, and intrinsic solubility. Unbuffered solubility, usually in water, means solubility of a saturated solution of the compound at the final pH of the solution (which may be far from pH 7 due to self-buffering)1. Buffered solubility also termed apparent solubility refers to solubility at a given pH, e.g. 2 or 7.5, measured in a defined pH-buffered system and usually neglects the influence of salt formation with counterions of the buffering system on the measured solubility value. Intrinsic solubility means the solubility of the neutral form of an ionizable compound. For neutral (non-ionizable) compounds all three definitions coincide. In many cases, the apparent solubility of an ionisable compound may be calculated from the intrinsic one (and vice versa), using the Henderson–Hasselbalch equation, although recently considerable deviations from Henderson–Hasselbalch have been reported 2.

Solubility plays an essential role in drug disposition, since the maximum rate of passive drug transport across a biological membrane, the main pathway for drug absorption, is the product of permeability and solubility. Poor solubility has been identified as the cause of numerous drug development failures. It is one of the components of the Biopharmaceutical Classification Scheme (BCS) and is particularly important for immediate release BCS class II drugs, for which absorption is limited by solubility (thermodynamic barrier) or dissolution rate (kinetic barrier). Further, if the solubility is incorrectly estimated, this can lead to erroneous interpretation of results in a number of in-vitro assays and weaken SAR 3-4.

Poor aqueous solubility is caused by two main factors: i) high lipophilicity and ii) strong intermolecular interactions which make the solubilization of the solid energetically costly. What is meant by good and poorly soluble depends partly on the expected therapeutic dose and potency. As a rule of thumb, a compound with an average potency of 1mg/kg should have a solubility of at least 0.1g/L to be adequately soluble. If a compound with the same potency has a solubility of less than 0.01g/L it can be considered poorly soluble.

Poor aqueous solubility can often be overcome by appropriate formulation work. However, this approach is expensive and without guarantee of success. It is much better to improve solubility by chemistry means through adequate changes in the molecule itself. To this end, it is desirable to determine the aqueous solubility of candidates as early as possible in the discovery process. Even though higher throughput assays have recently become available, the generation of high quality solubility data remains a relatively expensive and time consuming activity. Therefore, the development of models to predict the aqueous solubility of drug candidates from their chemical structure has attracted considerable attention. Predictive models based on molecular descriptors also help understanding what feature(s) limits solubility and can thus provide useful information to medicinal chemists.

Solubility Screening In Discovery And Development:

Solubility assays in discovery and development focus on different key questions. In lead identification, solubility assays are routinely used to rank-order hits, to flag compounds with potential liabilities, and to validate hits by comparing hit dose response values with apparent solubility values. Low solubility may indicate a response due to nonspecific inhibition by aggregate or precipitation formation. Further, compound solubility is measured under bioassay conditions to optimize assay conditions for the assay signal and to avoid potential screening errors due to solubility issues 5-7. Further along, in lead optimization, solubility information is used to guide chemist to overcome potential compound liabilities, to develop appropriate chemistry strategies, and to make informed decisions on potential development candidates. Historically, the introduction of large screening capacities for solubility in discovery was a result of increasing compound solubility limitations over the past decade, which caused a number of early and, more expensive, late candidate failures in some development programs 8-10. The trend towards lower solubility compounds was attributed to the introduction of High Throughput Screening (HTS) and of combinatorial chemistry as well as new targets that require more lipophilic molecules for efficient target affinity. As a result, more hydrophobic structures are synthesized. These are difficult to handle, to test, and to formulate and often have lower bioavailability in comparison to the large majority of marketed drugs. Since the majority of described HT-assays in discovery set-ups use dimethyl sulfoxide (DMSO) stock solutions for logistic reasons, compound solubility in DMSO and their long-term stability in DMSO, which can serious impact on screening strategies and results, has also gained considerable interest among discovery scientists7,11-12.

Needs And Trends In Solubility Measurement:

The historically strict boundaries between solubility assays performed in discovery and in development are starting to blur. Many organizations now realize that new workflows and technologies are required to fulfill the needs and interests of chemists, biologists and formulators in high quality solubility data with the ultimate goal to support, to improve and to speed up the compound and formulation selection processes. While a single, consistent methodology for solubility studies throughout the discovery and development process may at a first sight appear attractive and useful, the differences in workflow, speed, compound quantity and quality and particularly in the focus of solubility assays virtually preclude the set-up of a single solubility assay for both discovery and development. Nonetheless, the evolving common interest in solid form characterization, miniaturization, automation, and HT analytical techniques requires a more intense cooperation between discovery and development scientists. In early drug discovery, the focus of solubility assays is, phase-appropriate, still on short turnaround times and on keeping a drug in solution in an assay as opposed to determining its solubility limit or its solid state properties13. At the lead optimization level, however, this is changing. More systematic information on solid form properties together with physicochemical properties is now collected 14 and solubility assays are established that either use crystalline solids as starting material or give time for their formation during the solubility assay. As a consequence, the traditional line drawn between kinetic and thermodynamic solubility assays now seems artificial and probably has to be either replaced by a new terminology or discarded.

The challenge in development is now to test few compounds in large numbers of solvents and formulations that often vary considerably in physicochemical properties. Theoretically, these solvents might be stored either as solvent stock solutions 15or prepared adhoc from liquid or solid excipients when needed 16. The workflow for the handling of these solvents in development is usually not yet established and the required cooperation with compound management, informatics specialists, and assay automation specialists is often not in place17. For the future it will be important to identify appropriate workflows for storage, retrieval, and distribution of single solvents and mixtures that also address their physical and chemical stability throughout the process. Hardware capabilities to handle challenging solvents will be equally important and flexibility versus robustness and flexibility versus speed have to be considered carefully to optimize the workflow18-19.

Enabling strategies need to be established to test only those solvents with impact on decision making in drug discovery and development. In discovery, this may result in an extension of solvents to be tested, particularly in the lead optimization phase. Acceptable solubility ranges for oral absorption or classification of compounds have been defined20, however, the value of these water solubility data as a basis for compound selection and optimization efforts for ADMET properties is currently under discussion. It is clear that low water solubility in combination with other factors/liabilities does increase development times and needs more resources21, however, it is also well-known now that in vivo components (bile, phospholipids, pH) can positively influence the solubility of especially low soluble, ionizable compounds and improve their in vivo behavior. Therefore, solubility profiling in lead optimization in the future should probably also include in vivo components like bile as one additional compound to be considered in multidimensional compound profiling and optimization22-23.

Solubilization Mechanisms In The Gastrointestinal Tract

Although the underlying driver for solubility in the GI fluids is the aqueous solubility of the drug, the solubility in the GI tract may additionally be influenced by the pH profile, by solubilization via naturally occurring surfactants and food components, as well as by complexation with food and native components of the GI milieu. Since these additional influences can result in orders of magnitude changes in solubility (see Table 1 for some examples), it is worthwhile addressing them in some detail. The pH profile in the GI tract is of primary importance for drugs that can ionize in this range. Rearranging the Henderson–Hasselbalch equation (e.g. 24) we see that for a monobasic compound the concentration of acid required for saturation of the medium will be enhanced at pH values where ionization occurs:

Cs= Cs,0(1+10pH-pka) ------------------ Eq-1

where Cs,0 is the solubility of the non-ionized acid form(intrinsic solubility) and Cs is the total solubility (sum of intrinsic solubility and the existing concentration of ionized form) at the pH of interest. For a mono acidic compound the equivalent equation is:

Cs= Cs,0(1+10pka-pH) ----------- Eq-2

Table 1:Mean equilibrium solubility data in μg/ml for three drugs, illustrating the large differences between solubility in simple aqueous media and biorelevant media/ aspirates





(Intrinsic) aqueous solubility

1 a

≤6.9 b

≤5.0 d

Solubility in FaSSGF

1.4 a

9054 a

11,417 a

Solubility in HGFfasted

0.4 a

9025 a

8530 a

Solubility in FeSSIF

188 c

406–540 d

181–246 d

Solubility in HIFfed

412 c

476–989 d

160–254 d

a From Ref. 26.

b Intrinsic solubility (solubility of the non-ionized form) from Ref. 25.

c Numbers were extracted from the graphs of Ref. 27.

d Data vary with the aspirations times of HIFfed and with composition of FeSSIF 26.

The pH in the stomach in the fasted state has been the subject of many studies over the years and the general consensus is that in healthy adult humans the fasted pH usually lies in the range pH 1–3. Elevated pH can be observed in a modest percentage of elderly subjects due to waning ability to produce gastric acid. The effect is particularly pronounced in the Japanese population, although the incidence of achlorhydria there does appear to be falling with time27. In North Americans, elevated pH in the elderly is the exception rather than the rule28. On the other hand, gastric pH can be elevated by pharmacological interventions such as H2-receptor antagonists and proton pump inhibitors, which are used widely in Western populations. By contrast, hyper-secretion of acid is very rare, mostly associated with specific diseases such as Zollinger–Ellison syndrome 29. After meal intake, pH in the stomach usually rises due to buffering effects of the meal contents, and may initially reach values of up to 7, depending on meal composition. With the continuous secretion of gastric acid, the pH value then trends back down to baseline over a period of several hours30-31. In the small intestine the pH exhibits a profile, with lowest proximally and somewhat higher pH values in the distal regions. pH values in the duodenum in the fasted state tend to lie slightly below neutral (pH 6–6.5) 31-32. The pH in the proximal small intestine is influenced more by meal intake than the pH in the distal regions, as might logically be expected from the huge swings in pH observed in the stomach between the fasted and fed states. After meal intake, pH will be influenced by the chyme coming into the small intestine from the stomach. Thus, after meal intake the pH values may actually rise initially in the proximal small intestine. With time, as the incoming chyme becomes ever more acidic the pH will actually drop as low as 5–5.5, even in the jejunum31-32. Meanwhile, pH values in the distal ileum appear to remain stable at around pH 7.533. This is consistent with digestion and absorption occurring primarily in the proximal part of the small intestine: up to one-half of the small intestine can be removed without disturbing the ability to sustain nutritional balance 34. The pH in the proximal large intestine reverts to more acidic values, typically between 5 and 6.5 35, due to fermentation of undigested foodstuffs (cellulosics and the like) to short chain fatty acids (e.g. butyrate, propionate, acetate) by the colonic bacteria. The wide range of pH values encountered by ionizable drug substances within the GI tract suggests that large swings in solubility may occur, with implications for Cw (Eqs. (1) and (2)) and hence the efficiency of absorption. The second major influence on solubility in the GI tract is solubilization. Solubilization mechanisms include micellar solubilization by either native or co-ingested surfactants, binding to peptides or proteins and solubilization in lipid components of the meal. In the stomach, the source of surfactants is not so clear, although it has been consistently observed that the surface tension of gastric fluids is commensurate with a significant level of surfactant (e.g.26). In some subjects, the reflux of bile components into the stomach appears to be the source of surfactant behavior, but in others no bile components can be detected in gastric aspirates 36. In addition to native surfactants, meal intake offers the potential for solubilization of drugs during gastric residence. Macheras et al. have demonstrated that chlorothiazide and hydrochlorothiazide are well solubilized by casein micelles in milk 37 whereas more lipophilic compounds, such as indomethacin and diazepam, are additionally solubilized into the milk fat38. On the other hand, meal components can have an adverse effect on solubility if an insoluble complex with the drug is formed. The classical example here is complexation with calcium, which precipitates bisphosphonates and tetracyclines, rendering them insoluble and thus unavailable for absorption 39. In the small intestine the primary source of solubilization is clear — the bile components such as bile salt conjugates, phospholipids and cholesterol team up (additionally with lipolysis products in the fed state) to create mixed micelles that can solubilize lipophilic molecules very well. Indeed, correlations have been established for solubilization by mixed micelles as a function of logP for neutral compounds40. The concentration of mixed micelles is much higher after meal intake, as the gall bladder contracts in response to a meal and empties its contents into the duodenum at the level of the Sphincter of Oddi. In addition, in vitro studies indicate that the solubilization capacity of the micelles is enhanced by the incorporation of lipolysis products 41. It should be noted, however, that absorption of lipolysis products is generally completed in the jejunum and the bile salts are reabsorbed actively in the ileum 42, thus solubilization effects are restricted primarily to the upper small intestine. As there is a paucity of information in the literature about surface tension or surfactants in the colonic fluids, it is not possible to comment at this time on potential solubilization in this region. Other factors that can influence the capacity of the GI tract to dissolve drugs in a pharmacokinetically relevant way include the volume of fluids available in the region(s) of interest and the passage time of the drug/dosage from up to and through the regions where the drug is most efficiently absorbed.

Future directions

The ability to predict solubility in the upper gastrointestinal tract would clearly be advantageous to discovery and development programs in the pharmaceutical industry. Since direct measurement of luminal concentrations is cumbersome, recent efforts have been directed at determination of solubility in human gastrointestinal fluids and in developing media which can simulate these appropriately. With media already available or being developed for the upper gastrointestinal tract, the next logical step is to design media to represent conditions in the lower regions. Work is currently underway to characterize fluids collected from the proximal colon and to use these as a basis for design of the corresponding biorelevant media.

Intra-Lumenal Solubility Of Drugs

After oral administration, intra-lumenal drug concentrations influence the rate of appearance in plasma and, in certain situations they can determine the total amount reaching the general circulation. In turn, the solubility under gastrointestinal (GI) conditions sets the upper limit to the intra-lumenal concentration that can be achieved. The stomach, although not the primary site for drug absorption, provides the first site at which an orally administered formulation can quantitatively release its drug. For compounds highly soluble at gastric pH, complete dissolution can occur in the stomach. For such compounds, gastric emptying may well limit the subsequent rate of absorption from the small intestine (e.g. 46). For poorly soluble weak acids like ibuprofen 47 little dissolution will occur in the stomach. By contrast, the small intestine with its higher pH offers a more favorable environment for dissolution of acids. For ibuprofen and similar weak acids, emptying from the stomach becomes rate limiting to the onset of dissolution and hence absorption. For poorly soluble neutral compounds, dissolution will be slow in the gastric region and in many cases will not be complete before the drug reaches the first absorptive sites in the small intestine. Incomplete dissolution in the GI tract of such compounds can severely restrict their oral bioavailability. Finally, for poorly soluble weak bases, solubility is likely to be higher in the (preprandial) stomach than elsewhere in the GI tract. This can result in a supersaturation as the drug moves out of the stomach into the higher pH small intestine. Precipitation in the small intestine may result, though this process appears to be hindered by the bile components 48. In the fed state, the intra-gastric performance of immediate release tablets has to date been studied primarily in dogs. In these experiments, food components have been shown to delay the dissolution of highly soluble compounds during gastric residence49-50. Similar observations have been made very recently in humans51.

Drawbacks with direct measurements of intra-gastric or intra-intestinal drug concentrations are the specialized procedures used, the associated costs and ethical issues in terms of exposing humans to the procedure and drugs without any direct therapeutic benefit to the subject. As a result, data are usually collected from just a limited number of subjects and studies reported in the literature are few 52-54. One way to eliminate some of these drawbacks would be to use imaging techniques. However, such techniques would also be expensive to apply and, at best, they are still in their infancy with regard to this application 55. Another way to improve the cost:benefit ratio of the experiments is to collect human aspirates – without prior administration of the drug – and use them for measuring the parameters of interest.

Solubility Assays In Discovery And Development

Depending on the experimental set-up, solubility measurements determine either the kinetic or the thermodynamic solubility of compounds. In most cases, kinetic (non-thermodynamic) solubility measurements start from dissolved compound and represent the maximum (kinetic) solubility of the fastest precipitating species of a compound. The type of precipitating material is not determined and can be amorphous or crystalline, neutral or a salt, exist as a co-crystal or a combination of these possibilities. Kinetic solubility values are strongly time dependent and due to the degree of supersaturation that may occur, values are likely to over predict the thermodynamic solubility and are not expected to be reproducible between different kinetic methods 52. Precipitation from (organic) solution inherently favors metastable forms according to ‘Oswald's Rule of Stages' 53. Solubility assays in the majority of discovery set-ups determine kinetic solubility; however, equilibrium measurement principles are being introduced more and more into early discovery compound profiling. In contrast to kinetic solubility measurements, thermodynamic solubility assays are performed by dispensing a solid compound in a liquid. Thermodynamic (equilibrium) solubility represents the saturation solubility of a compound in equilibrium with an excess of undissolved substance at the end of the dissolution process. Thermodynamic solubility is often regarded as being the ‘true’ solubility of a compound and as the ‘gold standard’ for development needs. However, these values are not absolute numbers and depend, like kinetic values, on a multitude of compound properties and experimental factors.

For thermodynamic solubility measurement, the dissolution rate of compounds plays an important role, since the compound's crystal lattice has to be disrupted as part of the solubilization process. Consequently, the amorphous material or poorly crystalline material that is often generated in early discovery almost always exhibits higher solubility in all solvents compared to crystalline drug 54. Apart from crystallinity, the dissolution rate is affected by a number of additional factors, such as stirring rate, drug solubility, temperature, time, particle size, compound wettability, solvent viscosity (diffusion coefficient), and the polarity of the solvent 55. In practice, ‘equilibrium’ solubility is often determined only by single measurements, generally after 24–48 h. However, to really confirm that equilibrium has been achieved, compound solubility has to be constant with time and hence solubility measurements at several time points are necessary.

The key questions addressed by solubility assays in development focus on formulation and solid phase properties of compounds and on the identification of in vitro/in vivo correlations. In early development, thermodynamic assays are performed to confirm earlier kinetic solubility results, to rule out potential artifacts, and to generate quality solubility data with crystalline material to support the discovery scientist in the selection of potential clinical candidates. Re-testing of compound solubility of new batches in this and in subsequent development phases is a must. Frequently, amorphous or partially crystalline material in early batches is gradually replaced in subsequent large scale batches by polymorphs with increasing thermodynamic stability and higher purity which may in turn result in significantly lower compound solubility. 56-58.In early development, solubility screens are also performed in organic solvents. They are required to support initial salt and polymorph screening activities which aim to generate pure, stable, crystalline material in the most desirable physical form of the compound as early as possible for development 59 Additionally, organic solvent solubility data are very useful for formulators, process chemists, and analytical chemists for formulation, scale-up, and analytical method development, respectively 59. In much later phases, the solubility profile in organic solvents is necessary to develop efficient cleaning validation protocols for the cleaning of pilot plant and equipment, which comply with regulatory requirements. The identification and development of appropriate oral and parenteral formulations for animal and human studies is another. The environment in which a solubility assay is run and the primary focus of the assay, basically dictate how assays are currently set-up and performed in discovery and development. Qualitative and quantitative changes along the drug discovery and development process further determine how assays can be setup and run, which type of solubility can be measured, and how reliable solubility data can be. In discovery, during the period from lead identification to clinical candidate selection hundreds to thousands of different compounds are subjected to higher throughput assays in order to select and optimize for the most suitable compound. Compound availability at this stage is usually in the range of a few milligrams, and all assays compete for available compound. Optimization for solubility at this stage has to be performed in parallel to important other ADMET parameters and to biological target activity 60. Automation is a key element in this process, speeding up the assays, saving costs, reducing compound consumption and manual errors, and improving the consistency of the data. The huge numbers of compounds to be characterized in different assays also require standardized logistic procedures in compound handling and distribution. DMSO stock solutions have now been established as a de facto standard for compound storage and distribution to different assays, thus allowing HT testing, including solubility measurement. For solubility measurements, the introduction of DMSO stock solutions complicates compound profiling since DMSO may affect compound solubility itself60. Other challenges in the handling of DMSO stock solution have been discussed in detail by Lipinski and others 60, especially related to freeze/thaw cycles and possible related water uptake 60.In this phase solubility is measured in the microgram to low milligram/ml range principally in those solvents required for informed decisions or to support multidimensional optimization activities.

The standard set-up for solubility assays in development is based on solid compound, equilibrated in the solvent of interest for a defined time. Assays are designed to determine thermodynamic solubility. Thus solid state characteristics of the compound and impurities impact the result of the measurement to larger extent than is the case for kinetic solubility. Assays are typically performed in single vials and weighing procedures, necessary for handling of solid compounds, slow down the number of measurements which can be performed. In bigger pharmaceutical companies, the burden of weighing compounds is often shifted to central repository. However, this still requires significant resources and, compared to kinetic solubility measurements, restricts standard equilibrium solubility measurements in selected solvents to about 25–50 compounds a week (medium throughput) if handled by one specialist (including weighing). Automated weighing stations or other procedures for solid compound distribution may overcome the weighing bottleneck in the future. The solvents tested in development differ from those in discovery. Aqueous solutions are still important, but also organic solvents, oils, surfactants, polymers, or complex vehicles are tested. Compared to aqueous solutions, these solvents are often more demanding in that some are highly viscous, foam, stick to surfaces, evaporate fast or solidify under standard experimental conditions. Therefore they are often distributed manually. Analytics are usually performed by fast or ultra fast high performance liquid chromatography or LC-MS after removal of residual solid by filtration. For ionizable compounds in aqueous solutions the final pH is determined. Potential changes in the compound's polymorphic form during the experiment that may affect thermodynamic solubility should be characterized by analysis of residual solids with appropriate techniques such as X-ray, TGA, DSC, IR, RAMAN spectroscopy or terahertz spectroscopy. At the end of the preclinical phase, only one compound is usually left and solubility and dissolution studies are performed under strictly controlled conditions in a few solvents that are relevant for quality control or regulatory affairs. Compound consumption, assay volume, and concentration range tested now exceed those in early discovery by several hundred-to several thousand-fold Medium and high throughput solubility assays in discovery.

Kinetic and thermodynamic solubility assays

High throughput solubility assays in discovery are often kinetic solubility assays that are based on the detection of precipitation of compounds in aqueous solutions. Typically, small volumes of the stock solution are added incrementally to the aqueous (buffer) solution of interest until the solubility limit    is reached 60. The resulting precipitation is detected optically, and the kinetic solubility is defined as the concentration preceding the point at which precipitation occurs. 60, several modifications of kinetic assays have been described in above that differ in the dilution procedures and the detection methods. For example, in the original procedure 60 , DMSO stocks are added in small aliquots to the aqueous solutions spaced a minute apart until precipitation occurs. Alternatively, a series of specific concentrations may be prepared by dispensing the appropriate volume from a DMSO stock solution into separate vials 60. In both setups, the amount of DMSO in solution increases with substance concentration and may induce a higher solubility, with DMSO operating as a co solvent by changing the dielectric constant of the solution and helping to solvate the more lipophilic compounds. Solubility enhancement by DMSO, which can be dramatic, is highly compound specific60.

Different final DMSO concentrations in samples can be avoided if samples are first serially diluted in DMSO before they are added to aqueous solutions, although with this setup, the final DMSO concentration can still vary with the assay protocol in place and final DMSO concentrations of 0.33% ,0.5% , 1%, 2%, and up to 5% 60have been reported. Replacement of DMSO by other cosolvents, for example by ethanol or dimethoxyethanewith lower UV absorption in the low UV range, causes similar problems in terms of enhancing solubility and may also affect other compound properties such as compound permeability ; hence the final cosolvent and its concentrations in the aqueous solution should always be reported. In principle, there are two popular approaches to determining kinetic solubility, one by removing the precipitates and determining the concentration of  compound in solution and the other using precipitates as an indicator for the solubility limit of a compound.

The first approach separates solid material from the liquid phase after the incubation time by filtration through a filter plate. The filtrate is analyzed for compound in solution by a UV plate reader or HPLC analysis. Alternatively, undissolved compound may be removed by centrifugation and the supernatant is analyzed 60 . If results differ, this is mainly due to extremes in the molecular properties of the analyzed compound series, which either strongly accumulate at the filter surface or in the case of centrifugation float on the surface; the latter was often observed with hydrophobic compounds. The second category of newer solubility assays in discovery also uses compound stock solutions but, similar to some polymorph and salt screening workflows 60, solvent is removed by evaporation before the start of the assay. These assays combine the advantages of compound distribution via standardized stock solutions with those of solid state based equilibrium solubility measurements, thus several hundred compounds can be measured a week and compound consumption can be kept low.

The two newer approaches are definitively closer to‘classical’ thermodynamic assays than previous ‘kinetic’ solubility assays and a step into the right direction to generate quality solubility data early on. They focus more on solid state properties and on equilibrium solubility, but in contrast to thermodynamic assays, solubility values can not yet be linked to defined solid state properties of the compounds in these assays. In both approaches, the starting material generated by either precipitation or evaporation and the solid material present at the end of the study is not characterized and it can not be guaranteed that the polymorph relevant for development has really been formed during the experiment or that equilibrium has been reached. For both approaches, the overall throughput is reduced compared to ‘kinetic’ assays since additional compound handling steps are necessary and/or the overall incubation time is increased. In addition, plates need to be covered now since significant evaporation can occur particularly at higher temperatures In summary, solubility data from the new approaches are likely closer to those measured in later phases and may improve compound ranking and selection. From a practical point of view and compared to standard ‘kinetic’ assays, data may provide a better basis for the decision to move forward if the compounds possesses the required minimum acceptable aqueous solubility for oral activity in combination with permeability and potency60.

Potentiometric approaches

Potentiometric based approaches were first introduced into solubility profiling by Avdeef3. In analogy to octanol pH distribution (log D) profiles, determinations are based on the shift in pH values due to loss of compound, in the case of octanol by distribution into the organic phase and in the case of solubility by precipitation.

Currently two systems, pSol Gemini and Cheqsol, are commercially available. These differ partly in overall assay times and in the setup of the potentiometric titration procedure. The automatic potentiometric titration described by Avdeef 4 is relatively slow (8–24 h per determination) but allows generation of pH/solubility profiles with a single titration and with low compound consumption. The method has been evaluated in detail and reported results are comparable to those obtained by classical shake flask method 23. Recently compared a miniaturized equilibrium assay with the pSol method. pSol was judged to be very economical for ionizable compounds in terms of compound consumption (~100 microgram) since a whole pH/solubility profile can be determined with a single measurement. The method is also accepted by the FDA for assessing the solubility for BCS classification 3-4. pH/solubility profiles measured by the pSol method have been referred to as the industry ‘gold standard’ 23 and to have major advantages compared to pH solubility profiles determined in a series of buffer systems. Both methods pSol and Cheqsol are limited to ionizable compounds, which are dissolved and re-precipitated by shifting pH during titration. Solid state characteristics of precipitated compounds are usually not determined in the standard setup, therefore results have to be interpreted with care. Future extensions of both methods regarding determination of solid state properties seem to be possible. The huge dynamic solubility measurement range of seven orders of magnitude (nanograms to hundreds of milligrams) makes both methods attractive for scientist in both discovery and development.

A simplified “pSOL procedure”, termed “chasing equilibrium” that allows reduction in measurement times was first described by Stuart et al. 61. The equilibrium solubility in this method is actively sought by “changing the concentration of the neutral form by adding HCl or KOH titrants and monitoring the rate of change of pH due to precipitation or dissolution”. pH/solubility profiles of compounds are not directly measured with this method and are accessible only via application of Henderson–Hasselbach relationships; potential aggregation phenomena are not considered. This method is reported to determine equilibrium, kinetic, and intrinsic solubility within 20–80 min which is faster than the pSOL method.

In contrast to “chasing equilibrium”, the pSol method additionally gives access to the whole pH/solubility profile of an ionizable compound and offers the potential to identify pH dependent supersaturation and aggregation phenomena. In our experience, the generation of pH/solubility profiles is sometimes necessary to support interpretation of permeability and distribution results in discovery and early development and a version of the described systems that allows parallel measurement of several samples would be highly desirable in the future. Recently, we used the pSol method for a detailed analysis of solubility supersaturation effects to identify a more rational approach for getting crystalline material in aqueous solutions in cases where standard crystallizations procedures did not work.

Crystal Engineering For Improving Solubility And Dissolution Rates

Drug molecules with limited aqueous solubility are becoming increasingly prevalent in the research and development portfolios of discovery focused pharmaceutical companies. Molecules of this type can provide a number of challenges in pharmaceutical development and may potentially lead to slow dissolution in biological fluids, insufficient and inconsistent systemic exposure and consequent sub-optimal efficacy in patients, particularly when delivered via the oral route of administration. Advances in the pharmaceutical sciences have led to the establishment of a number of approaches for addressing the issues of low aqueous solubility. These strategies for improving and maximizing dissolution rate include micronisation to produce increased surface area for dissolution, the use of salt forms with enhanced dissolution profiles , solubilisation of drugs in co-solvents and micellar solutions , complexation with cyclodextrins  and the use of lipidic systems for the delivery of lipophilic drugs. Although these techniques have been shown to be effective at enhancing oral bioavailability, the success of these approaches is dependent at times on the specific physicochemical nature of the molecules being studied 62-67.

Crystal engineering approaches, which can potentially be applied to a wide range of crystalline materials, offer an alternative and potentially fruitful method for improving the solubility, dissolution rate and subsequent bioavailability of poorly soluble drugs. The ability to engineer materials with suitable dissolution characteristics, whilst maintaining suitable physical and chemical stability provides a strong driver for the utilisation of new and existing crystal engineering approaches to drug delivery system design. The challenges of low aqueous solubility provide an ideal situation for the application of crystal engineering techniques for improving bioavailability, whilst also developing stable and robust pharmaceutical products. Therefore potential utility of crystal engineering as an approach for designing efficacious dosage forms for poorly soluble drugs. Crystal engineering is taken as the design of molecular solids in the broadest sense with the aim of tailoring specific physical or chemical properties. The subject of the approaches is therefore to present those diverse aspects of crystal engineering which may be used to manipulate the solubility and/or dissolution rate of the parent molecular components in the crystalline state. At the centre of these available approaches is the need to change surface and molecular assembly in equilibrium with a solution. Consequently, it covers the possible ways, this may be achieved from recent developments in the study of molecular solids and reviews topical issues such as habit modification, polymorphism, solvation, co-crystal formation and surface modification. Particular attention will be paid to the area of co-crystallisation, which is an emerging area of strategic importance to the pharmaceutical sector.

Crystal engineering in drug development

Crystal engineering has been described as the ‘exploitation of non-covalent interactions between molecular or ionic components for the rational design of solid-state structures that might exhibit interesting electrical, magnetic, and optical properties’. It is also recognized that it ‘is becoming increasingly evident that the specificity, directionality, and predictability of intermolecular hydrogen bonds can be utilized to assemble supramolecular structures of, at the very least, controlled dimensionality’. Supramolecular chemistry has grown around Lehn's analogy that ‘supermolecules are to molecules and the intermolecular bond, what molecules are to atoms and the covalent bond’ . If molecules are built by connecting atoms with covalent bonds, solid-state supermolecules (crystals) are built by connecting molecules with intermolecular interactions. The fundamentals of crystal engineering were described in detail under the term ‘molecular engineering’ 68. Modern crystal engineering initially began as a method for understanding the regioselectivity and product distribution in solid-state molecular reactions, termed topochemistry 68. This field has developed rapidly, particularly with the arrival of modern crystallographic techniques such as four circle diffractometers in the early 1970's followed by the introduction of area detector technology. Crystal engineering now encompasses many aspects of solid-state intermolecular interactions, structure prediction, control and rationalisation, as well as the synthesis of novel molecular building blocks and crystalline materials, and may be broken down into the components of analysis and synthesis. Within the notion of a crystal as a supramolecular entity lies certain key ideas central to the activity of crystal engineering. These are the nature of the crystallisation process at a molecular level, crystal packing, molecular interaction and directed molecular recognition, which will all be explored to some extent in this review and which should provide some understanding of crystal engineering approaches as a means of addressing the challenges of low aqueous solubility

It is clear that the crystal and particle engineering strategies have notable potential to strengthen the available methods for addressing problems of low aqueous solubility of drug substances. These methods are applicable not only to molecules of a specific physical and chemical nature, but to a wide range of crystalline materials, although a comprehensive knowledge of drugs at the molecular level is required to determine the appropriate approach to improving solubility and dissolution rate.


The use of a prodrug strategy as a chemical/biochemical approach to overcome various barriers which can hinder drug delivery, including solubility69. Now focus is on use of prodrugs to overcome poor water solubility, not only of already marketed drugs with solubility limitations, but more important, how the prodrug strategy should become an integral part of the drug design. Why prodrugs now, when the concept has been around for many years? One main reason is the recent slump in the number of drugs approved by worldwide regulatory agencies. This, in turn, can be attributed to changes in drug candidate identification methodologies implemented years earlier, the conservative nature of the pharmaceutical industry, and ever tougher regulatory and safety standards. Because of new high throughput receptor based screens/assays (HTS) initiated in the late 1980s and the use of combinatorial chemistry approaches to drug design, many drug candidates during this era had pharmacokinetic/pharmacodynamic and physical/chemical properties that limited their chance of being developed into pharmaceutical products. Solubility has been identified as a critical parameter and one amenable to manipulation via a prodrug strategy69.

Many still question the use of a prodrug strategy as a problem solving technique. Some of these concerns are valid, namely, the additional time and cost when a prodrug approach is needed to solve a specific formulation or delivery problem. It can be argued that if the prodrug strategy became an integral part of the drug design paradigm, little additional time and expense is needed. The prodrug becomes the NCE-that happens to have an active metabolite. According to Hedge and Schmidt 69, of the 24 NCEs approved in 2005, 19 were small molecules, while five were polypeptides or macromolecules (biotech products). Of the 19 small molecules, two were clearly identified as prodrugs (10.5%). There was one PEGylated antiviral approved that was probably a prodrug (raising the percentage to 15.8%). There were two other small molecule antivirals that owed their activity to being phosphorylated and are therefore technically prodrugs but not always valued as such. If one includes all five molecules, 26.3% of all drugs approved in 2005 were prodrugs, with 15.8% clearly by design. Similar evaluations over longer time periods show that a significant number of drugs marketed over the last 15 years were prodrugs. As stated earlier, there many successful examples of parenteral, water-soluble prodrugs of poorly water-soluble drugs. In fact, other than prodrugs to overcome permeability barriers, they are by far some of the best prodrug examples. Surprisingly, there are few marketed prodrugs designed to improve the oral delivery of sparingly water-soluble drugs. This is, however, an active area of interest and one that is likely to lead to many new products in the future.

Prodrugs continue to be an exciting area of research. The heightened interest of late comes from the fact that more and more drug candidates present significant delivery challenges, with poor water solubility being an increasingly frequent problem. The relatively high percentage of recently approved drugs that are, in fact, prodrugs supports claims for the heightened recent interest in prodrugs.

Salt Formation To Improve Drug Solubility

Salts of acidic and basic drugs have, in general, higher solubilities than their corresponding acid or base forms. Salt formation to increase aqueous solubility is the most preferred approach for the development of liquid formulations for parenteral administration 70. For solid dosage forms, dissolution rates of salt forms of several weakly acidic compounds under gastrointestinal (GI) pH conditions were much higher than those of their respective free acid forms. He attributed the higher dissolution rate of a salt to its higher solubility (relative to the free acid form) in the aqueous diffusion layer surrounding the solid. Pronounced differences were observed in rates and extents of absorption of novobiocin 70 and tolbutamide as compared to their respective sodium salts. Monkhouse and coworkers 71-72 reviewed physicochemical and biopharmaceutical advantages of salts over their free acid or baseforms. The interest in salt formation has grown greatly over the past half a century and, in recent years, it has become the most commonly applied technique of increasing solubility and dissolution rate in drug product development.

The primary reason for the increased interest in salt formation is that with the progress in medicinal chemistry and, especially due to the recent introduction of combinatorial chemistry and high-throughput screening in identifying new chemical entities (NCE) , the solubility of new drug molecules has decreased sharply . While a value of less than 20 μg/mL for the solubility of a NCE was practically unheard of until the 1980s, the situation has changed so much that in the present day drug candidates with intrinsic solubilities (solubility of neutral or unionized form) of less than 1 μg/mL are very common . Lipinski 70 reported that 31.2% of a group of 2246 compounds synthesized in academic laboratories between 1987 and 1994 had solubility equal to or less than 20 μg/mL. According to the recent experience of the present author, approximately one-third of new compounds synthesized in medicinal chemistry laboratories have an aqueous solubility less than 10 μg/mL, another one-third have a solubility from 10 to 100 μg/mL, and the solubility of the remaining third is N100 μg/mL. With such a predominance of poorly water-soluble compounds, careful attention must be paid to identification and selection of optimal salt forms for development. In certain cases, salt formation may not be feasible due to physical and chemical properties of NCEs. In other cases, even though salts can be synthesized, they may not serve the purpose of enhancing dissolution rate and bioavailability. It is important that the reasons behind such situations are understood.

Despite major advantages of the use of salts, only limited attention has been paid historically to the selection of optimal salt forms for pharmaceutical product development. At the beginning of drug development programs, salts were often selected based on ease of synthesis, ease of crystallization, cost of raw material, etc., and no systematic studies to evaluate their physicochemical properties, such as physical and chemical stability, process ability into dosage forms, solubility and dissolution rate at different pH conditions, etc., were conducted. If a salt was later found to be suboptimal for the desired formulation or if problems developed, it was often difficult to change the salt form without delaying the drug development program, since it required repeating most of the biological, toxicological, formulation and stability tests that had already been performed. For most practical purposes, identification and selection of salt forms of NCEs still remain a trial and error process. One major objective of the present article is to review the basic principles of salt formation and how salts influence solubility and dissolution rate in a comprehensive manner, such that they can be easily applied to the development of drug substances as well as dosage forms. Efforts will be made to indicate the application of such principles in screening various salt candidates for a NCE, identification of optimal salt form, and ultimately formulation of dosage forms using the selected salt. Wherever possible, advantages and disadvantages of salt forms relative to their respective free acid or base forms will be presented.

One particular issue with the use of salts in drug development is that, while salts are usually prepared from organic solvents, they are destined to encounter aqueous environment (water, humidity) during dosage form development and, in case of an orally administered tablet or capsule, at the time of dissolution in GI fluid. Therefore, a perfectly good salt isolated from an organic solvent may not behave well in an aqueous environment due to low solubility, conversion to free acid or base forms, poor stability, etc., thus limiting its use in dosage forms.

Principles of salt formation and salt solubility

The aqueous solubility of an acidic or basic drug as a function of pH dictates whether the compound will form suitable salts or not and, if salts are formed, what some of their physicochemical properties might be. pH–solubility interrelationships also dictate what counterions would be necessary to form salts, how easily the salts may dissociate into their free acid or base forms, what their dissolution behavior would be under different GI pH conditions, and whether solubility and dissolution rate of salts would be influenced by common ions [15,16].

Practical considerations of salt solubility in dosage form design

The topic of how salts can be used advantageously in the development of pharmaceutical dosage forms has been reviewed elsewhere and is beyond the scope of the present article. Here, only a few points regarding how the solubility principles described in the present article may be applied to develop solution formulations and in resolving stability issues with solid dosage forms are discussed.

Liquid formulations

Determination of pH–solubility profiles of NCEs with different counterions provides information with respect to what counterion is best suited to optimize (often maximize) drug solubility in a liquid formulation. In selecting a salt form for development both as solid and liquid dosage forms, care should be taken to accommodate solubility needs of the liquid formulation. This is because a salt may have acceptable dissolution rate from a solid dosage form, but its solubility may not be adequate for the liquid formulation. Effects of counterions used to adjust tonicity or as buffering agents on drug solubility are also important considerations70.The use of cosolvent may also be helpful when the pH adjustment alone does not provide solubility, since the solvent may modify the solubility profile by increasing the S0 value. However, one should be careful that the overall solubility of the salt is not decreased due to the solvent effect. Many of the problems associated with liquid formulations are due to precipitation of free acid or base forms of drugs. If the pH of the solution is adjusted such that the solubility is no longer controlled by the salt form, special attention must be paid to buffering the system strong enough that there is no significant shift in pH. This is because the slopes of pH–solubility curves at pH>pHmax for a basic drug and pH<pHmax for an acidic drug could be very steep and a small change in pH may have an adverse effect on drug solubility 70.

Micro environmental pH of salts in solid dosage forms

As mentioned earlier, high aqueous solubility in the diffusion layer at the dissolving surface is responsible for the high dissolution rate of a salt. The pH in this layer may be different from that in the microenviroment of a solid dosage form, and, if the microenvironmental pH of a formulation is significantly different from that of a salt, a conversion from the salt to free acid or base may occur in the products in accordance with pH– solubility and pHmax principles described earlier. The conversion of ifetroban sodium to its free acid form decreased dissolution rates of tablets during accelerated stability testing 70, and the conversion of the maleate salt of an experimental drug to free base resulted in volatilization of the relatively lower-melting base and the consequent decrease in drug assay 70. Therefore, in developing dosage forms of a salt, the potential for any conversion to the free form needs to be considered and excipients should be selected such that no such conversion occurs. If necessary, the microenvironmental pH should be adjusted 70.

Of approximately 300 NCEs approved by the FDA during the 12-year period from 1995 to 2006 for marketing, 120 were in salt forms. Although the salt formation was sometimes utilized to crystallize and purify drug substances, most were prepared to improve the solubility of drugs. Salts are often used to increase drug solubility in parenteral and other liquid formulations. Salt formation is also the most common approach of increasing solubility, dissolution rate and ultimately bioavailability of poorly water-soluble ionizable drugs in solid dosage forms. In applying the physicochemical principles of salt formation to enhance solubility and dissolution rate, care must be taken to consider and, if possible, avoid the conversion of salts to their respective free acid or base forms. These conversions may also take place during the determination of dissolution rates of salts in reactive media. Salts are also prone to common-ion effect that may lower solubility and dissolution rate, and they may undergo self-association to form supersaturated solutions. These factors, which can also occur in vivo, should be evaluated carefully during salt selection and dosage form development.

Looking forward to the future, salts formation will remain the primary approach to improve solubility and dissolution rate of poorly water-soluble acidic and basic drugs. However, as the potential drug candidates are becoming extremely water-insoluble, it might not be possible in many cases to form optimal salts. Careful analysis of the interrelationship of intrinsic solubility, pKa and possible salt forms will be necessary to minimize unsuccessful attempts to prepare salts. Stronger anions and cations will be commonly utilized to enable salt formation. Even when a salt is formed, it might not be able to enhance bioavailability of drugs adequately. As mentioned earlier in this article, salts may precipitate out in the GI fluid after oral administration into their free acid and base forms. For newer drugs, the precipitates may not redissolve rapidly due to their very low aqueous solubilities.

To overcome these limitations with salt formation and salt dissolution, it is expected that alternative formulation approaches, such as solubilization, complexation, solid dispersion, lipid-based drug delivery systems, etc., to enhance bioavailability of poorly water-soluble will replace salt formation for many compounds. There is also an increased awareness of the effect of microenvironmental pH on the dissolution of salts from solid dosage forms. The pH-modifiers will be more commonly used in solid dosage forms to minimize conversion of salts to their respective free upon storage and also due to pH effects in the GI fluid. The situation will become even more complex in the development of solutions for parenteral administration. For a compound with the intrinsic solubility 1 μg/mL, even a 1000-fold increase in solubility by salt formation will give a concentration only of 1 mg/mL, which might not be adequate for the purpose of dosage form development. In such a case, the salt formation may be combined with another solubilization strategy to obtain adequate drug solubility.


The delivery of poorly water-soluble drugs has been the subject of much research, as approximately 40% of new chemical entities are hydrophobic in nature and solubility of active pharmaceutical ingredients (API) has always been a concern for formulators, since inadequate aqueous solubility may hamper development of parenteral products and limit bioavailability of oral products.  This review gives a conceptual idea about Bioavailability enhancement methods, solubility prediction methods, solubility assays, crystal engineering and salt formation of API which is now area of research and will be helpful in drug discovery and development.


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About Authors:


Lecturer , Dept. of Pharmaceutics Mandsaur Institute of Pharmacy, Rewas-Dewda Road, Mandsaur-458001, M.P
E-mail: santosh14july@rediffmail.com
Phone: +919826953642

Mr. Mahesh Bhat

Mr. Mahesh Bhat (Lecturer)
Mandsaur Institute of Pharmacy, Rewas-Dewda Road, Mandsaur-458001, M.P

Mr. Alok Savla

Mr. Alok Savla
Mandsaur Institute of Pharmacy, Rewas-Dewda Road, Mandsaur-458001, M.P

Mr.Emmanuel Toppo

Mr.Emmanuel Toppo (Lecturer)
Mandsaur Institute of Pharmacy, Rewas-Dewda Road, Mandsaur-458001, M.P

Dr.Suresh Purohit

Dr.Suresh Purohit (Principal)
Mandsaur Institute of Pharmacy, Rewas-Dewda Road, Mandsaur-458001, M.P



Eswar GsnkRao's picture

Thanks for giving us a nice article which is practical.
Will U plz see the below link revealing the request of one of our Pharmainfo.net users. Could U help her if possible.

eswar :-)


ESWAR :-) 

Muralee Krishnane's picture

there are various methods to increase the solubiliy of drugs,however your study helps to understand the mechanism correctly and to select suitable method.congrats

KB's picture

Dear Payghan,

Congratulations on your recent review on the Potential of Solubility in Drug Discovery and Development. However, as one of the inventors of the CheqSol technique, I feel that you have not given accurate comments on the method of chasing equilibrium that was first described by myself and my colleague Martin Stuart.

We market this assay under the name CheqSol (Chasing Equilibrium Solubility). It is not correct to describe CheqSol as a “simplified pSOL” procedure. The discovery of the principles underlying CheqSol was made independently of the pSOL methodology. The experimental designs are different. The data handling is different and the calculations are different. None of the principles of pSOL is used in CheqSol.

Referring to CheqSol, you state that “pH/solubility profiles of compounds are not directly measured with this method”. You later imply that the pSOL does make a direct measurement of the pH vs. Solubility profile. We believe this statement to be incorrect – pSOL measures only the intrinsic solubility by curve fitting. An extrapolated pH vs. Solubility profile is then generated by calculation using the measured pKa and the intrinsic solubility, in much the same fashion as CheqSol.

We know from our own experience of using pSOL that while it is pretty slow, it can produce accurate measured values for equilibrium solubility using small sample weights. The pSOL software has some nice graphics and what-if features. However, the possibilities for experimental design are quite limited, and it always seeks a result from curve-fitting. As a result some interesting compound behaviours are overlooked. In CheqSol, by real-time monitoring of the pH change we are able to observe changes due to precipitation, supersaturation and polymorphism as they happen rather than assuming the behaviour will fit a pre-selected model. This has revealed insights into solubility and precipitation phenomena that could never have been learned from pSOL.

Not only has CheqSol enabled us to make extremely accurate measurements of equilibrium solubility that have been independently validated. It also provides a supersaturation ratio between kinetic solubility and equilibrium solubility measured during the same experiment, and has enabled us to identify three different classes of compound that we have called chasers (which dissolve and precipitate slowly), non-chasers (which dissolve slowly but precipitate quickly) and super-dissolvers (which dissolve quickly but precipitate slowly). We believe that knowing the class a molecule falls in will be very useful during formulation. CheqSol also tells us dissolution and precipitation rates for compounds held near equilibrium. Because experiments can be maintained at virtually constant pH for hours, CheqSol can detect abrupt drops in solubility that occur when solids convert to more stable forms, and we have now discovered two examples where this form change is caused by the creation of completely new polymorphs [for example, Llinàs, A. Box, K J. Burley, J C. Glen, R C. Goodman, J M. A new method for the reproducible generation of polymorphs: two forms of sulindac with very different solubilities. J. Applied Crystallography, 2007, 40(2), 379-381].

Other papers in the CheqSol series are:

Box, K J. Comer, J E. Using Measured pK(a), LogP and Solubility to Investigate Supersaturation and Predict BCS Class. Curr. Drug Metab., 2008, 9(9), 868-878.

Llinàs, A. Glen, R C. Goodman, J M. Solubility challenge: can you predict solubilities of 32 molecules using a database of 100 reliable measurements? J. Chem. Inf. Model. 2008, 48(7), 1289-1303.

Llinàs, A. Burley, J C. Prior, T J. Glen, R C. Goodman, J M. Concomitant hydrate polymorphism in the precipitation of sparfloxacin from aqueous solution. Crystal Growth and Design, 2008, 8(1), 114-118.

Llinàs, A. Burley, J C. Box, K J. Glen, R C. Goodman, J M. Diclofenac Solubility: Independent Determination of the Intrinsic Solubility of Three Crystal Forms. J. Med. Chem.; 2007, 50 (5), 979-983.

Sköld, C. Winiwarter, S. Johan Wernevik, J. Bergström, F. Engström, L. Allen, R. Box, K. Comer, J. Mole, J. Hallberg, A. Lennernäs, H. Lundstedt, T. Ungell, A-L. Karlén, A. Presentation of a Structurally Diverse and Commercially Available Drug Data Set for Correlation and Benchmarking Studies. J. Med. Chem. 2006, 49(23), 6660-6671.

Box, K J. Völgyi, G. Baka, E. Stuart, M. Takács-Novák, K. Comer, J E A. Equilibrium vs. kinetic measurements of aqueous solubility, and the ability of compounds to supersaturate in solution - a validation study. J. Pharm. Sci. 2006, 95(6), 1298-1307.

Stuart, M. Box, K. Chasing equilibrium: measuring the intrinsic solubility of weak acids and bases. Anal. Chem. 2005 (77(4)) pp 983-990.

I hope this information on CheqSol is helpful to you.

Yours Truly,

Prakruti's picture

My Page : http://www.pharmainfo.net/prakruti
nice article

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