The research has shown that successful drugs tend to have a "drug-like" property. At the In Vitro level, the "drug-like" mainly refers to PK characteristics and safety, which can be viewed as the result of the balance between the SPR (structure-property relationship) and SAR (structure-activity relationship). The SPR study of drugs is an emerging drug discovery strategy, such as solubility, lipophilicity, dissociation constant (pKa), stability, and other property studies that significantly impact In Vitro and In Vitro pharmacology. For example, in the early stages, scientists can understand and optimize more factors affecting the experiment based on the physicochemical properties and help determine compound priority and promote the optimization of the molecular structure. This process also informs the research team of the factors affecting development loss to optimize the design to improve the compound's performance and success. As below illustrates, the physicochemical properties of a drug are significant in the whole ADME study.
Solubility is a critical parameter used to guide compound selection and optimization during drug discovery. The advantage of early solubility screening is that compounds with poor absorption or bioavailability that resulted from poor solubility should be excluded promptly before more expensive screening experiments are performed. Therefore, the determination of solubility values should be performed as early as possible during drug development. Different types of solubility data are required for the characterization of compound properties in different R&D stages. Because of the large number of test articles, even with a small number of compounds in the early R&D stage, kinetic solubility can be one of the critical methods used for compound ranking. As compounds enter the later stage, different crystal forms are usually selected for the study, and thermodynamic solubility testing is a commonly used method in this stage. DMPK provides these two high-throughput screening methods for solubility measurement. Details on the experimental system are shown below:
Lipophilicity expressed as distribution coefficient (log D) in octanol/aqueous buffer, is an important physicochemical parameter influencing processes such as oral absorption, brain uptake, and various pharmacokinetic (PK) properties. For example, a drug exerts its therapeutic effects by interacting with specific receptors present inside the body. Physicochemical properties of a drug, such as lipophilicity and water solubility, play a crucial role in making the drug target-drug receptor interaction. DMPK provides services of high-throughput lipophilicity testing as shown below:
The dissociation constant (pKa) of compounds affects the mode of drug existence in the body fluid. It is vital to get the pKa of compounds in the drug discovery and development stages. For example, it can help the scientist know how to perform the salt form screening. Due to the correlation of pKa, solubility, and lipophilicity, pH adjustment can be performed to improve the compound's solubility once the pKa value is obtained. Both potentiometric titration and spectrophotometry are routinely used in DMPK, and Sirius T3 instruments are applied to measure pKa.
From a physiological point of view, the stability of the drug is affected by the In Vitro environment, especially the pH of the gastrointestinal tract. Therefore, the stability of the drug is essential in different pH environments. Compounds should be stable enough to ensure they are not degraded in the gastrointestinal system before they enter the systemic circulation, allowing sufficient time to pass through the gastrointestinal tract into the blood circulation and bringing about ideal bioavailability. DMPK provides the buffer stability testing of a compound in a different medium, as follows:
Compounds that Log P-values within the range of 0-5 can be experimentally determined by the classic Shake-Flask method, which is fast and accurate for high lipophilicity compounds (Log P > 5). Two chromatography test methods were developed for detection aiming at efficient and accurate data acquisition. The verification data are shown below: