[Good laboratory practice of equilibrium solubility measurement]. / Az egyensúlyi oldhatóság meghatározásának helyes gyakorlata.

The biggest part of my PhD work was the standardization of the classical saturation shake-flask solubility method. During the experiments we examined systematically which parameters have significant influence on the solubility value and how large experimental error (standard deviation) is caused by them in the solubility method. Hydrochlorothiazide was used as model compound. Modification in temperature, sedimentation time, composition of aqueous buffer and the technique of separation of solid and liquid phases were found to influence the equilibrium solubility results strongly. However, variations in the amount of solid excess and stirring time were found to have less influence. Based on this standardization study, we developed a new shorter (36 hours) protocol for measurements of equilibrium solubility of drug molecules. The new protocol was validated with the aid of 6 structurally different compounds. The equilibrium solubility was measured by both (standard and new) protocols. The results were in good agreement, so the shorter protocol can be applied to measure the equilibrium solubility of drug compounds.

[Good laboratory practice of equilibrium solubility measurement II. Study of pH-dependent solubility of ionizable compounds]. / Az egysúlyi oldhatóság meghatározásának helyes gyakorlata II. Ionizálható vegyületek pH-függo oldhatóságának vizsgálata.

In this paper the pH-equilibrium solubility profiles of ionizable drugs are presented. 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. In the case of monoprotic bases, namely papaverine, promethazine and propafenone the experimental equilibrium solubility data precisely follow the theoretical HH curve 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 can be easily interpreted with the formation of different salt compositions. The significance of pH control and the effect of the salt form (e.g., fumarate) was also investigated. It is 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.

Study of equilibrium solubility measurement by saturation shake-flask method using hydrochlorothiazide as model compound.

The experimental conditions that affect equilibrium solubility values measured by the classical saturation shake-flask method have been examined, using hydrochlorothiazide as a model compound. Modifications in temperature, sedimentation time, composition of aqueous buffer and the technique of separation of solid and liquid phases were all found to influence the equilibrium solubility results strongly. However, variations in the amount of solid excess and stirring time were found to have less influence. In the light of these observations, a new, shorter protocol has been developed for measurements of equilibrium solubility, together with recommendations for good analytical practice. The equilibrium solubilities of five other drugs were measured to verify the new protocol.

Equilibrium versus kinetic measurements of aqueous solubility, and the ability of compounds to supersaturate in solution--a validation study.

A novel potentiometric procedure has recently been described for rapid measurement of equilibrium aqueous solubility values of organic acids, bases, and ampholytes that form supersaturated solutions. In this procedure, the equilibrium solubility 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 in a process called Chasing Equilibrium. In this article, we seek to validate the procedure against a shake-flask protocol for solubility determination. A set of 16 small organic compounds, covering a wide range of solubilities was chosen for the study. Interestingly, while 10 compounds in the study were found to chase equilibrium, the others did not. Kinetic solubility data was also collected. It was noted that kinetic solubility was consistently higher than equilibrium solubility for chasers, but correlated well with equilibrium solubility for nonchasers. The ratio of kinetic to equilibrium solubility indicated a compound's ability to form supersaturated solutions.

Study of pH-dependent solubility of organic bases. Revisit of Henderson-Hasselbalch relationship.

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 pK(a) value and the intrinsic solubility are accurately determined when the HH relationship is used to predict the pH-dependent aqueous solubility of drugs.