Physiochemical properties of drugs Using the Sirius T3 to make measurements

Physiochemical properties A drug’s physiochemical properties affect its liberation, absorption and distribution. Four important physiochemical properties are: acid dissociation constants and pK a ; partition and distribution coefficients and logP and logD; solubility and logs; dissolution rates. These may be determined experimentally. Sometimes they are calculated using molecular modelling. They do not provide information about a compound’s effect as a drug, but they do tell us about what might happen to the compound in the body. Physiochemical properties of drugs Instrumentation Reminder:LADME are the stages that happen when a medicinal drug is taken (usually in a formulation): Liberation – Absorption – Distribution – Metabolism – Excretion Various experimental techniques may be used. Developments in computer-controlled (robotic) instruments, and computer programmes (to carry out complex calculations) have streamlined the measurements. Click below for more information. Physiochemical properties

Samples for analysis Who for? Samples come from pharmaceutical companies and university research departments. What types of samples? Two types are received: Large numbers of structurally similar compounds. The clients are trying to find answers to questions such as “How do structural differences affect logP values?” This is important since the drug must stick to cell membranes, but not too tightly. One or two formulations containing the medicinal drug. The clients want to know how their physiochemical properties compare so that the optimum formulation can be found. The start of the analytical journey Samples arrive at Sirius Analytical Services from all over the globe. They arrive carefully packaged and with instructions about what analyses the client wants. Information about the samples and analytical requests are logged on a computerised system. Physiochemical properties of drugs Receiving samples Reminder:A medicinal drug needs the optimum physiochemical properties so that the processes of liberation, absorption, distribution, metabolism and excretion can happen effectively. Formulations are mixtures of the drug with other ingredients. These can physiochemical properties such as dissolution rates.

Preparing for analysis Tiny quantities No matter what physiochemical property is being determined the first step is to weigh a suitable quantity of the compound. Less than a milligram (0.001 g) is needed. Setting up the instrument Regular calibration checks are made on the instrument. Apart from weighing the sample all other operations are carried out by a computer- controlled robot. For a given physiochemical property determination, such as pK a or logP, the appropriate programme must be selected to ensure the correct sequence of operations. The instrument The analytical unit is described in an earlier video clip. It contains a pH electrode, a UV detector, a variable speed stirrer and a bundle of tiny plastic tubes. The tubes deliver measured volumes of liquids such as water, acid, base and octan-1-ol. Volumes as small as cm 3 can be measured out. Physiochemical properties of drugs Reminder:Key physiochemical properties of a medicinal drug or formulation that are determined are: acid dissociation constants and pK a partition coefficients and logP solubility and logs dissolution rates

Determining pK a Most drugs ionise in aqueous solution. They are weak acids or weak bases. The dissociation constant, K a, for a weak acid is given by: and Using these equations we can derive: Physiochemical properties of drugs So for a solution in which In the titration of a monobasic, [A − ] = [HA] the pH of the solution at the halfway to the end- point point of the titration graph equals pK a. However, a number of assumptions and approximations. Complex computer- programmes used in the instrumental method reduce these considerably and give a more accurate value for pK a. pH Volume of KOH(aq) added pKapKa half-way point end point

Determining logP In drug discovery and development, lipophilicity is usually expressed by the partition between water and octan-1-ol. The partition coefficient, P, of a drug is given by: where [drug molecule] o = concentration of drug in octan-1-ol [drug molecules] w = concentration of drug in water Physiochemical properties of drugs In the traditional shake flask method, a sample of the drug is shaken with a octan-1-ol/water mixture and its concentration in each layer is determined. Drugs that ionise in water The situation is more complex with drugs that ionise in aqueous solution – and that is most of them. These drugs are characterised by their distribution constant, D. Its value depends on pH. Determining logD at various pHs allows logP to be calculated. Where, [drug molecule] o = concentration of drug in its molecular form in octan-1-ol; [drug molecule] w = concentration of drug in its molecular form in water; [drug ion] w = concentration of drug in its ionised form in water. The distribution constant depends on pH. A plot of pH against logD gives a curve with a horizontal section at lower pH values. In this range, distribution is not pH dependent and logD = logP.

Determining logs It has been said that low solubility is top of the list of undesirable properties of a potential medicinal drug. So being able to measure solubility and, if necessary, modify a compound to alter its solubility without affecting its therapeutic properties is important. Equilibrium solubility The equilibrium solubility of a compound is the concentration of a saturated solution in contact with an excess of undissolved solid. Traditionally, excess compound is shaken with a solvent until a saturated solution is produced with an excess of the solid compound present. It is an accurate but very time-consuming method. Kinetic solubility Pharmacologists also measure kinetic solubility. Precipitation is brought about by, for example, changing the polarity of the solvent. The concentration at which a precipitate first appears is measured. This is the compound’s kinetic solubility. Kinetic solubility of a weak acid The kinetic solubility in water of a drug that is a weak acid is determined by: dissolving the acid in a known volume of base, e.g. potassium hydroxide solution; adding an acid, e.g. hydrochloric acid, until a precipitate is detected (the UV sensor ‘sees’ the first formation of cloudiness). Rather than solubility, logs is usually calculated. Physiochemical properties of drugs

Reporting back Once the required measurements have been made the results are reported back to the client. Physiochemical properties of drugs Reminder:Key physiochemical properties of a medicinal drug or formulation that are determined are: acid dissociation constants and pK a partition coefficients and logP solubility and logs dissolution rates