We perform the characterization of the most relevant physicochemical parameters to ensure adequate profiles for compound development and as first indicators of “drug-likeness” of new chemical entities (NCEs).
Information about these properties is also valuable when planning optimum conditions for any biological assay and may be applied to any other field where they may be relevant. For instance, the water solubility of any test substance may be determined under OECD105 or the partition coefficients under GLP may be obtained in relation to Environmental Risk Assessment (ERA).
- Solubility is an important parameter in drug development as it is a limiting factor for the free-to-interact fraction of the compound in the gastrointestinal fluids, plasma and other matrices in the body and together with permeability determines the BCS class of a compound. We can determine solubility in a wide range of conditions:
- Kinetic solubility: Determined by spiking DMSO-stock solution into buffer-system at any desired pH with LC/PDA/MS analysis in a high throughput format.
- Thermodynamic solubility: It is determined using the traditional “shake-flask” method in any aqueous media and using LC/PDA/MS analysis.
- pH-Solubility profiles: For oral dosage forms, a comprehensive evaluation pH-solubility profiles helps to establish the boundaries of best absorption and bioavailability. Through comprehensive analysis of the molecule structure, crystal/salt form and other related properties, our experts may build a full range pH-solubility profiles for any product.
- OECD 105 test: Water solubility following the OECD 105 guidelines are determined for all types of solid compounds.
- Dissolution rate: Dissolution rate is a kinetic assay used to measure the speed at which the solid dissolves in aqueous conditions and showing the compound behaviour at different pHs as well as in different feeding situations. This is relevant for orally administered drugs to predict if their absorption is likely to be affected by food. To this aim gastrointestinal tract (GIT) dissolution media Fasted State Simulated Intestinal Fluid (FaSSIF) and Fed State Simulated Intestinal Fluid (FeSSIF), are used to simulate fasted or fed state human intestinal fluids, respectively. Determination of preliminary small scale dissolution rate may be done using Sirius T3 or HPLC in any desired condition.
- Lipophilicity (logP/D): Lipophilicity refers to the tendency of a compound to partition between a lipophilic organic phase and a polar aqueous phase. Lipophilic compounds generally have a higher permeation across biological membranes, but they are also linked to lower solubility and unspecific binding. Lipophilicity is represented either as partition coefficient, logP or distribution coefficient, logD. Since the majority of known drugs are at least partly charged in physiological pH, logD is more accurate descriptor of compound lipophilicity as it describes the partition of both un-ionised and ionised forms of the molecule.
We provide three different methods for determining lipophilicity:
- Shake-flask: The standard procedure is adapted to DMSO solutions so very low amount of compound is needed.
- Chromatography: It is based on the correlations built from retention measurements and the lipophilicity values for a set of standards.
- Potentiometry (Sirius T3): log Po/w values are obtained from the difference between the aqueous pKa of the species and the apparent pKa determined from dual phase titrations (n-octanol/KCl 0.15 M).
OECD 107 or 123 tests: We can determine the logKow under OECD 107 or 123 guidelines under GLP. The logDpH is determined using the shake-flask methodology (with HPLC quantification) at a given pH or via chromatography.
- PKA: Ionization constants (pKa) values are fundamental to determine the biopharmaceutical and distribution characteristics of drugs at the different pHs of the biological fluids.
We perform the determination of the acidity and basicity pKa of any desired compound by potentiometry (Sirius T3).
- HYGROSCOPICITY: Hygroscopicity is the ability of a material to absorb moisture from surrounding environment which can have an impact on the physical and chemical stability a compound. Different grades of hygroscopicity are established by the different Pharmacopoeias and its study is compulsory in the characterization of development products. We determine hygroscopicity using dynamic vapor sorption (DVS) and following the European Pharmacopeia guidelines.
- THERMAL ANALYSIS: The complete thermal characterization of a solid form is necessary for establishing the expected behaviour in relation to heat and to select the most appropriate solid form for development. We perform the determination of melting point and complete thermal analysis (solid-solid-transitions, moisture content, dehydration) by differential scanning calorimetry (DSC) and thermogravimetry (TGA).