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6.2 Physicochemical Assessments 143
form during this test. The FDA approved the two forms of the medication, and in 1999, it was even-
tually made available for sale [140].
Mebendazole is an anthelmintic drug with a benzimidazole structure. Mebendazole has three
different forms, and the difference in solubility of these three different forms causes changes in the
activity of the drug. In physiological media, the solubility order is Form B > Form C > Form A. Form
B is toxic due to its high solubility and consequent bioavailability, while form A nonanthelmintic
activity due to its lesser solubility. Form C is the favored form in pharmaceuticals because of its
high solubility, which guarantees good absorption without the risk of toxicity [141].
Different methods are used for the characterization of polymorphs. These are:
● Hot stage microscopy.
● Thermal analysis: Differential thermal analysis (DTA), differential scanning calorimetry
(DSC), and thermogravimetric analysis (TGA).
● Spectroscopy.
● X-ray [140, 142].
6.2.6 Molecular Weight
The atomic weights (or atomic masses) of every atom in a molecule add up to the molecular mass
(MW) of a substance, which is also referred to as the molar mass or molecular mass and is usually
given in Daltons (Da). The molecular weight (MW) of a substance influences its membrane perme-
ability, which in turn influences its intestinal absorption and tissue distribution, especially when it
comes to permeability via the BBB. The atomic weights of each atom in the chemical formula are
summed up to determine the MW. Mass spectrometers and other analytical tools are useful for
obtaining accurate MWs [134].
There is often a general trend (even sometimes correlation) toward increased lipophilicity as MW
increases [143]. Comprehensive research has demonstrated that permeability decreases as MW
increases, leading Lipinski to suggest a 500 Da cutoff for certain medications. Some molecules,
MW > 500 Da, are absorbed, though. In certain instances, MW is purposefully raised (and may
surpass 500 Da) through the creation of a prodrug to enhance permeability. For instance, the
dianionic medication that is the active ingredient is poorly absorbed, while the ester prodrug
olmesartan medoxomil is effectively absorbed [125] (Figure 6.8).
Figure 6.8 Olmesartan’s conversion from prodrug to active medication.
6 ADMET and Physicochemical Assessments in Drug Design144
6.2.7 Number of Hydrogen Bond Donors (HDB) and Acceptors (HDA)
The drug’s distribution, metabolism, excretion, and absorption (ADME) are all impacted by
HBs [144]. A drug’s potency in forming HBs with water is reflected in how easily it may be
transported from water to a nonpolar environment. This process has a significant impact on both
passive permeability and in vivo distribution. Drugs that are in their neutral form must have HBs
with water that are energetically more favorable than HBs between their solid-state molecules in
order for them to have good aqueous solubility. The fact that most medicines’ intracellular unbound
concentrations cannot be determined in vivo is a substantial difficulty in the design of new
therapies. HBDs can result in extremely poor solubility, permeability, and bioavailability, especially
for substances in the upper end of the molecular weight property range. On the other hand,
compounds that solely consist of HBAs and do not have any formal donor groups can nevertheless
maintain good permeability, which in turn allows for BBB penetration and bioavailability [145].
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