Solid Forms and Pharmacokinetics

Abstract

In the world of pharmaceutics, a very close relationship exists between ADMET, pharmacokinetic parameters and the physicochemical properties of a drug. They are decisive factors dictating the therapeutic performance of the drug in vivo. Physicochemical parameters (such as dissolution properties and solubility) act as “chauffeurs” guiding the drug through the different barriers in the body which significantly affect its absorption. During early development, these parameters are optimized to some extent by structural modifications in the molecule, but in most cases this approach is limited, as they result in the loss of efficacy. Solid state modifications either by electrostatic interactions (such as in salts) or non-covalent interactions (such as in co-crystals) have evolved as an excellent alternative that can efficiently alter the dissolution rate and affect its pharmacokinetics. They can be custom designed, not only to alter the mode of administration, but can also optimize the release-action profiles of a drug for more patient-friendly dosages. In addition to the bountiful merits, solid state alterations can also prove to be life threatening. An altered form in a specific lot/generic batch can lead to varied concentrations of the drug in plasma which can potentially cross the therapeutic window leading to no efficacy or toxicity. Again, unanticipated co-crystallization amongst the formulation components during manufacture or storage can lead the formation of a form with unacceptable physicochemical and pharmacokinetic properties that is detrimental to the health of the patient. Therefore, detailed solid state screening during drug development is seminal in every discovery program.

Pharmaceutical aspects of salt and cocrystal forms of APIs and characterization challenges

“…Moreover, a new salt or cocrystal is eligible for an extension of patent rights: the approval will also be simpler because of the existence of previous knowledge coming from the early pharmaceutical form [22]. The portfolio of API salt forms offers several strategies to alter the therapeutic significance of drugs, by changing their dissolution, absorption, and other physico-chemical and pharmacokinetic aspects [23][24][25]. It is noteworthy that the aims of new API salt forms research are mainly focused on improving the dissolution properties and consequently the absorption of drugs.…”

Advanced Methodologies for Pharmaceutical Salt Synthesis

“…The formation of hydrates can be difficult to monitor and control during wet massing, fluid bed drying, and aqueous film coating. ,,, Similarly, it has been documented that salts containing chloride ions (54% of the salts approved between 1995 and 2006) might exhibit reduced dissolution rates due to the common ion effect, as gastric and intestinal fluids (jejunum) are rich in chloride. , Salts are an excellent way for enhancing the pharmacological properties of a drug, but the sole focus on the improvement of dissolution rate and solubility properties of drugs can sometimes be counterproductive. This is of particular importance as this improvement can occasionally lead to adverse effects by increasing the accumulation of the drug beyond the equilibrium solubility, if not considered carefully …”

“…Albeit solubility is the predominant concern in drug development, a choice needs to be made between the highest solubility and the highest stability. This becomes a particular challenge in cases when the maximally soluble form suffers from stability issues due to, e.g., hydrolysis, which is a common degradation problem. ,, …”

“…This is of particular importance as this improvement can occasionally lead to adverse effects by increasing the accumulation of the drug beyond the equilibrium solubility, if not considered carefully. 23 Among numerous options, cocrystals (Figure 3) have opened a new door in relation to drug development as they are not limited, unlike salts, to ionizable drugs. Furthermore, cocrystal formation can be an effective approach to create new intellectual property in the pharmaceutical industry and thus prolong the life cycle of APIs.…”

“…This becomes a particular challenge in cases when the maximally soluble form suffers from stability issues due to, e.g., hydrolysis, which is a common degradation problem. 5,8,23 Another common approach entails the application of amorphous solids in drug products; however, crystalline drug materials are preferred to meet the requirements in terms of thermodynamic properties such as purity, stability, and means of processing. 12 Furthermore, for systems including solvates, hydrates, and inclusion compounds, physical stability is an important factor to consider since hydrates are considered a nemesis for crystal engineering due to the "promiscuity" of water.…”