This chapter describes how electrodes work, giving examples of how to use them. It also describes advice on how to select the best electrodes for a given application, and how to maintain them for optimum performance. A pH electrode built into the probe senses the change in pH, which is directly proportional to the ammonium ion content of the sample. pH, chloride, fluoride, sodium, and most other ion-selective electrodes sense the ion "directly." Ion-selective electrodes are potentiometric sensors; their electrode potential when placed in a solution is related to the activity of a selected ion in that solution. Membrane electrodes have membranes which are selectively permeable to a particular ion. The ammonia diffuses through a gas-permeable membrane at the tip of the probe and dissolves in an internal filling solution, thereby changing the pH. Like membrane electrodes, solid-state electrodes can become coated with impermeable precipitates.

The purpose of this study was to better understand the dissolution properties and precipitation behavior of pharmaceutical cocrystals of poorly soluble drugs for the potential for oral administration based on a small-scale dissolution assay. Carbamazepine and indomethacin cocrystals with saccharin and nicotinamide as coformers were prepared with the sonic slurry method. Dissolution of the poorly soluble drugs indomethacin and carbamazepine and their cocrystals was studied with a small-scale dissolution assay installed on a SiriusT3 instrument. Two methodologies were used: (i) surface dissolution of pressed tablet (3 mm) in 20 mL running for fixed times at four pH stages (pH 1.8, pH 3.9, pH 5.4, pH 7.3) and (ii) powder dissolution (2.6 mg) in 2 mL at a constant pH (pH 2). Improved dissolution and useful insights into precipitation kinetics of poorly soluble compounds from the cocrystal form can be revealed by the small-scale dissolution assay. A clear difference in dissolution/precipitation behaviour can be observed based on the characteristics of the coformer used.

Two weak bases, PG-300995 (anti-HIV agent) and NSC-639829 (anti-tumor agent), whose log S – pH profiles had been previously published, but whose pKa values had not been reported, were analyzed using a method which can determine pKa values from log S – pH data. This “SpH-pKa” technique, although often practiced, can result in inaccurate pKa values, for a variety of reasons. The operational SpH-pKa values were compared to those predicted by MarvinSketch (ChemAxon), ADMET Predictor (Simulation Plus), and ACD/Percepta (ACD/Labs). The agreement for the sparingly-soluble PG-300995 was reasonably good. However, a substantial difference was found for the practically-insoluble NSC-639829. To probe this further, the pKa of NSC‑639829 was measured by an independent spectrophotometric cosolvent technique. The log S - pH profile of NSC-639829 was then re‑analyzed with the independently-measured pKa. It was found that the equilibrium model which best fit the solubility data is consistent with the presence of a monocationic NSC-639829 dimeric species below pH 4. This illustrates that an independently-determined accurate pKa is critical to mechanistic interpretations of solubility-pH data. Apparently, the Henderson-Hasselbalch equation holds for PG-300995, but not NSC-639829.

A value of 8.8 μg/mL was measured for the intrinsic solubility of indomethacin. Evidence of an amorphous form with a solubility of about 77 μg/mL was also obtained. Solubility measurements were conducted using the CheqSol and Curve Fitting methods using a maximum pH of 9. It is also demonstrated that a published intrinsic solubility of 410 μg/mL was in error due to decomposition of indomethacin at pH 12. The decomposition of indomethacin at pH 12 was investigated. Decomposition products comprising p-chlorobenzoic acid and 5-Methoxy-2-methyl-3-indoleacetic acid were isolated and characterised.

Purpose The aim of this poster was to study the impact of several simulated lung fluid (SLF) media on the physicochemical properties of a selected group of inhaled drugs. Physicochemical properties such as pKa, logP solubility and dissolution rates were measured at different conditions using protic and aprotic salts in phospholipid and surfactant systems to observe the impact of the media on the physicochemical properties of the drug. Sample properties were also compared with a standard phosphate buffer media. Methods Measurements were performed at, 37°C and 0.15M ionic strength using the SiriusT3 physchem profiling instrument. The SiriusT3 is an automated titration platform with in‐situ UV fibre‐optic spectroscopy. Small quantities of drug material were used in 1 to 3 mL volumes to determine pKa, logP, solubility and dissolution behaviour at pH=7.0. Media were prepared using sodium dodecyl sulphate (SDS) surfactant and a commercial phospholipid preparation (Curosurf ® , Takeda Pharma) with the addition of several protic and aprotic salts. Experiments were also carried out with phosphate buffer.

This article briefly introduces a number of experimental methods that can be used to investigate supersaturation and precipitation of small-molecule drugs. Methods include solubility measurements by pH-metric methods; controlled supersaturation studies by pH-metric and UV methods; studies of the solid state using polarised light microscopy; aqueous dissolution under changing pH conditions; and biphasic dissolution. Examples illustrate how the results may be used to guide decision-making during formulation.

SUMMARY A method is described to study the dissolution behaviour of inhalation product API in both phosphate buffer and simulated lung fluids. INTRODUCTION The aim of the study was to measure the dissolution characteristics of various active pharmaceutical ingredients (APIs) contained in inhalation products, using novel low volume assays. Samples were compared in a standard phosphate buffer and in a simulated lung fluid (SLF) media. EXPERIMENTAL METHODS The dissolution performance of six APIs used in inhalation products (budesonide, indacaterol, pranlukast, rofleponide, salmeterol and zafirlukast) was measured at 37°C using two novel dissolution technologies. In the first technique, the SiriusT3 1 was set up to run powder dissolution assays in 2mL volumes with quantitation using in-situ UV fibre-optic probes. The second technique used a surface dissolution imaging system (Sirius SDI 2 ) allowing direct measurement and visualization of dissolution events at or near the surface of the API in realtime. It uses a pixellated array to capture UV-light transmitted through a flow-cell where a compact of the API is introduced to the flow. Dissolution measurements were compared using standard phosphate buffer and a simulated lung fluid media containing 1% sodium dodecyl sulphate (SDS). RESULTS AND DISCUSSION Powder dissolution results in phosphate buffer ranged between 1% released for pranlukast up to 10% for zafirlukast. There was a marked increase in dissolution performance in SLF medium for zafirlukast (up to 20% release, Figure 1) and for salmeterol (up from 12% release in phosphate buffer to 18% in SLF). However, for some APIs (e.g., indacaterol) there was no increase or only a marginal increase in dissolution performance. The increase in dissolution in SLF could be attributed to increased wettability in the presence of a surfactant in combination with surface active properties of the API itself. The use of a compact and real-time UV imaging of the surface (Figure 2) confirmed the increased accessibility of the media at the interface when surfactant was present. Figure 1. SiriusT3 dissolution profiles showing the mass released versus time for the six drugs studied in the presence of SLF studied in comparison with the phosphate buffer media Figure 2. Surface Dissolution Imaging, with 0.2 mL/min flow rate.

Methods Hundreds of experiments of different types were run over a period of five years to investigate supersaturation and precipitation of small molecule drugs in aqueous solution. The results of this work have led to a better understanding of the types of behaviour that a drug can exhibit. The experiments undertaken comprised the following: solubility measurements by pH‐metric methods; solubility by shake‐flask; controlled supersaturation studies by pH‐metric and UV methods; studies of the solid state using polarised light microscopy; aqueous dissolution under changing pH conditions; and biphasic dissolution. Results To help rationalize a complex set of behaviours, supersaturation and precipitation phenomena have been classified into four principal classes. Examples are provided of experiments and results that demonstrate the behaviour expected with each class. The first class comprises aqueous solutions in which a drug is supersaturated but no precipitate is present. The other classes comprise supersaturated solutions in which the drug is also present as precipitate in the LLPS (liquid‐liquid phase separation) form, supersaturated solutions in which the drug is precipitated as a crystalline solid, and a fourth class comprising solutions in non‐aqueous or partially non‐aqueous media in which the concentration of drug dissolved is higher than the aqueous solubility; this behaviour is exemplified by drugs in lipid‐based formulations. Conclusion A simple 4‐case chart has been developed to classify the behaviour of drugs in supersaturated solution and during precipitation. It will provide a structured approach for evaluating the behaviour of compounds during formulation and in determining viable formulation strategies.

SUMMARY A method is described to study the intrinsic solubility of drug compounds using novel pH-metric solubility methods and the ability of lipid based formulations to enhance solubility. INTRODUCTION The purpose of this study was to determine the intrinsic solubility enhancement of several drug compounds in the presence of a lipid based formulation at 37°C. The ratio of the components in the formulation were varied to investigate the effect of composition on the solubility of the compound. The results may help to evaluate the suitability of a lipid based formulation for drug delivery. EXPERIMENTAL METHODS The solubility of six ionizable drug compounds of varying lipophilicity was studied using the CheqSol technique 1 in the presence of Labrasol®. CheqSol was used for the determination of the solution concentration of the free (acid or base) form of a compound during an acid-base pH titration using the principles of mass and charge balance. The drug compounds were first dissolved at a pH where they were most soluble (high pH for acids, low pH for bases), at varying concentrations of Labrasol®. This volume was then titrated towards the compound’s pKa until the neutral species precipitated. Labrasol® is a water dispersible surfactant used in Self-emulsifying Formulations (SELF) and is capable of enhancing the apparent solubility by a micellar mechanism. The apparent solubility (LogS) was first plotted against the concentration of Labrasol®, which yielded a straight line graph. The magnitude of the slope may be related to the ability of Labrasol® to enhance the solubility of the compound. The compounds studied include propranolol, metoclopramide, orphenadrine, pramoxine, sulfamerazine and nitrofurantoin. RESULTS AND DISCUSSION For the compounds tested here, the addition of the Labrafac TM in absence of the surfactants (ratio 0:1), did not affect the intrinsic solubility of the compounds. A relatively high interfacial surface tension between the aqueous medium and Labrafac TM , which caused the immiscibility, may inhibit any solubilization by the lipid vehicle or partitioning of the compound into the lipid. Only when the surfactant mixture (Lab-Cap) was introduced did the intrinsic solubility begin to increase. The higher surface activity of the Lab-Cap mixture, may have reduced the surface tension between the aqueous medium and lipid vehicle, thereby enabling a solubilization/ partitioning process. For two of the compounds (metoclopramide and propranolol), the maximum intrinsic solubility was found when Labrafac TM was absent altogether (ratio 1:0), which suggested a very low affinity between these compounds and the lipid vehicle. For sulfamerazine, the intrinsic solubility was largely unaffected by the presence of the surfactants or lipid, which again suggested a very low affinity between this compound and the excipients used in this study. But, for three of the compounds (pramoxine, orphenadrine and diclofenac), the intrinsic solubility maxima were found where Lab-cap and Labrafac TM were both present, but at differing ratios (0.2:1, 0.2:1 and 5:1, respectively). This showed that the composition of the formulation can be optimized for compound solubility. For metoclopramide and propranolol, the largest enhancement in solubility was observed where the phase of the formulation was an emulsion, according to Figure 1. Conversely, the solubility of orphenadrine and pramoxine was enhanced the greatest where the formulation consisted of two immiscible phases. Furthermore, the intrinsic solubility of diclofenac was enhanced by a factor of 64 and showed significant enhancement where the formulation was either immiscible or an emulsion. Figure 1. Intrinsic solubility of the compounds was plotted against the ratio of the surfactant mixture(LabCap):lipid vehicle (Labrafac TM ) CONCLUSION Using CheqSol, it was possible to readily evaluate the solubility of ionizable compounds at elevated temperatures in the presence of lipid based formulations, which enabled optimization of the composition of the formulation to attain maximum solubility enhancement. In general, the solubility enhancement improved with the lipophilicity of the compound. However, the extreme enhancement observed for diclofenac may also be influenced by the stabilization of the oily/amorphous form. The ratio of surfactant:lipid vehicle, at which maximum solubility enhancement was observed, varied between the compounds. For those compounds that have a propensity to form oily droplets (pramoxine, orphenadrine and diclofenac), the ratio was biased towards the lipid vehicle (Labrafac TM ). REFERENCES 1. Box, K.; Comer, J. E.; Gravestock, T.; Stuart, M., New ideas about the solubility of drugs. Chem Biodivers 2009, 6 (11), 1767-88. ACKNOWLEDGEMENTS We thank Gattefossé, Saint-Priest (Lyon, France), for the supply of lipid based formulations used in this study.

This paper describes a low volume, in vitro apparatus for investigating the dissolution and precipitation behaviour of active pharmaceutical ingredients (APIs) under a wide range of experimental conditions and dissolution media. The apparatus has automated and dynamic pH control, allowing the simulated passage of drugs through the gastrointestinal tract (GIT). Experiments can be performed in the presence of biorelevant media and excipients, providing information related to the predicted behaviour of APIs under physiological conditions. The technique is described in detail and results are presented for a number of neutral, basic, acidic and ampholytic drug compounds.

SMi's fifth annual ADMET Conference, held in London, included topics covering new developments in the field of ADMET. This conference report highlights selected presentations on ADME optimization in drug discovery; targeting drugs to the brain; predicting bonds that might be attacked during metabolism; treating Caco-2 membranes with vinblastine to enhance P-glycoprotein interactions; predictive ADMET in hit-to-lead optimization; structure-based studies of ADMET targets; an accelerated process for integrated drug development; building hypotheses in lead selection and optimization; supersaturation effects; the prediction of drug-drug interactions; developing a mechanism-based pharmacokinetic/pharmacodynamic model; drug transporter assays in drug discovery; time-dependent inhibition screens in early drug discovery; the system-dependent inhibition of CYP enzymes; the integrating predictive toxicology framework OpenTox; high-content analysis for predictive cytotoxicity testing; and emerging in vitro toxicity assays.

Experimental methods are described for measuring solubility and supersaturation of ionisable drugs by potentiometric titration. Characteristic properties are described for compounds that do and do not supersaturate. Graphic examples are shown of the variation of neutral species concentration vs. time during the precipitation of imipramine, dipyridamole and piroxicam from aqueous solution, and of metoclopramine in the presence of PVP and taurocholate. The graphs illustrate how the neutral species may be held in solution at concentrations greater than the equilibrium solubility for extended times, that differ according to the solid state form and the effect of additives.

SMi's fifth annual ADMET Conference, held in London, included topics covering new developments in the field of ADMET. This conference report highlights selected presentations on ADME optimization in drug discovery; targeting drugs to the brain; predicting bonds that might be attacked during metabolism; treating Caco-2 membranes with vinblastine to enhance P-glycoprotein interactions; predictive ADMET in hit-to-lead optimization; structure-based studies of ADMET targets; an accelerated process for integrated drug development; building hypotheses in lead selection and optimization; supersaturation effects; the prediction of drug-drug interactions; developing a mechanism-based pharmacokinetic/pharmacodynamic model; drug transporter assays in drug discovery; time-dependent inhibition screens in early drug discovery; the system-dependent inhibition of CYP enzymes; the integrating predictive toxicology framework OpenTox; high-content analysis for predictive cytotoxicity testing; and emerging in vitro toxicity assays.

In this paper the pH-equilibrium solubility profiles of six organic drugs are presented. The equilibrium solubility values were determined using the saturation shake-flask and the Chasing Equilibrium Solubility (CheqSol) methods. Results obtained by the two methods are in good agreement. The aim of the present work was to study the validity of the Henderson-Hasselbalch (HH) relationship in the case of structurally diverse weak bases. The significance of pH control and the effect of the salt form (e.g., fumarate) was also investigated. In the case of monoprotic bases, namely papaverine, promethazine, propafenone and ticlopidine the experimental solubility data precisely follow the HH equation until the limit of salt solubility. The common ion effect on salt solubility was found to be significant at low pHs. Deviation from the HH equation in the case of dibasic quetiapine hydrogen fumarate and the ampholyte desvenlafaxine hydrogen fumarate can be easily interpreted with the formation of different salt compositions. It was concluded that precise pH control is essential in shake-flask solubility measurements. It is also critical that the pKa value and the intrinsic solubility are accurately determined when the HH relationship is used to predict the pH-dependent aqueous solubility of drugs.

Methods are described for detecting precipitation of ionisable drugs under conditions of changing pH, estimating kinetic solubility from the onset of precipitation, and measuring solubility by chasing equilibrium. Definitions are presented for kinetic, equilibrium, and intrinsic solubility of ionisable drugs, supersaturation and subsaturation, and for chasers and non-chasers, which are two classes of ionisable drug with significantly different solubility properties. The use of Bjerrum Curves and Neutral-Species Concentration Profiles to depict solubility properties are described and illustrated with case studies showing super-dissolving behaviour, conversion between crystalline forms and enhancement of solubility through supersaturation, and the use of additives and simulated gastrointestinal fluids.

It is useful in drug research and development to know whether and to what degree drugs are absorbed and transported in the human body. One way to find out is to measure drug absorption in vivo in humans, for it certainly tells people what they want to know– that the drug was absorbed. These measurements are made during the late-stage development of drugs that are likely to come to market. When investigating the properties of newly discovered drugs, it is also useful to assess whether they may be absorbed. However, in vivo experiments during the discovery process are out of the question for a number of reasons – not enough drug is available, the cost of experiments is very high, and the toxicity of the drug has not yet been assessed.

In this paper the validation of pKa determination in MDM-water mixtures is presented. The MDM-water mixture is a new multicomponent cosolvent mixture (consisting of equal volumes of methanol, dioxane and acetonitrile, as organic solvents) that dissolves a wide range of poorly water-soluble compounds. The cosolvent dissociation constants (p(s)Ka) of 50 chemically diverse compounds (acids, bases and ampholytes) were measured in 15-56 wt% MDM-water mixtures by potentiometric or spectrophotometric titration and the aqueous pKa values obtained by extrapolation. Three different extrapolation procedures were compared in order to choose the best extrapolation in MDM-water mixture using a sub-set of 30 water-soluble compounds. The extrapolated results are in good agreement with pKa values measured in aqueous medium. No significant difference was found among these extrapolation procedures thus the widely used Yasuda-Shedlovsky plot was proposed for MDM cosolvent also. Further we also present that the single point estimation based on measurement in 20%/v MDM-mixture using a general calibration equation may be suitable for rapid pKa determination in the early phase of drug research.