*3.2.6 Hygroscopicity and deliquescence*

Hygroscopicity can be demonstrated as the potency of a drug or salt to gain moisture or water vapour. Compounds can be interacted with moisture by retaining it in bulk or absorbing it on the surface, capillary condensation, and chemical reactions. Atmospheric conditions and the surface area of drug substances are responsible for the amount of moisture absorption. Moisture level variation highly affects the stability, compressibility, and flow properties that's why these attributes should be studied cautiously.

The moisture uptake measurement is done by Karl Fischer titration, Thermogravimetric analysis (TGA), and gas chromatography techniques. As per European Pharmacopoeia, four separate grades of hygroscopicity are defined when a drug substance is stored at 80% relative humidity and a temperature of 25°C for 24 h. The four classes of hygroscopicity are described here as per the above-mentioned storage conditions [48, 49].

**Class I:** Non-hygroscopic drug substances, when no moisture is detected below 90% relative humidity condition.

**Class II:** Slightly hygroscopic drug substances are those when their weight increases between 0.2% but less than 2% w/w in presence of moisture.

**Class III:** Hygroscopic drug substances produces weight increases between 0.2% and less than 15% w/w.

**Class IV:** Very hygroscopic when the weight increases more than 15% w/w.

Moisture is a significant element that may have an impact on the stability of potential medications and their formulations. Hydrolysis is frequently seen by the adsorption of water molecules onto a potential medication (or excipient). Water molecules have hydrogen bonds and high polarity, this property of water made it absorb the surface of drug substances and affects crystal habit properties, compaction, flow properties, dissolution rate, lubricity, and drug permeability across biological membranes. Therefore, to get rid of the hygroscopicity problems it is necessary to select an appropriate adjuvant, stabile drug compounds, and optimum storage conditions during the preformulation phase. The substances absorb moisture to the highest quantity and liquefy themselves. Deliquescent substance absorbs moisture to a greater extent and liquefies themselves hence, they dissolve solids and leave a thin water film on their surface. This process is linked with relative humidity conditions, this condition measured by vapour diffusion and heat transport rates [18].

#### *3.2.7 Pseudo-polymorphism*

Pseudopolymorphism refers to the phenomenon in which the drug molecules get incorporated into the crystal lattice of solids. The solids can exist in different crystal forms known as pseudo polymorphs and the process is pseudopolymorphisms. These forms contain a secondary heterostructure within the crystal lattice, with the same chemical makeup (examples are water, solvent, co-former, etc.). These forms are also known by other names like hydrates, solvates, and cocrystals, and FDA considered them polymorphs [50].

#### **3.3 Preformulation solubility parameters**

A significant barrier to product development is solubility. Poor drug solubility (shown in **Table 4**) is a common cause of medication discovery and development failure.

Insufficient solubility can hinder the molecule's capacity to be developed since it can make it difficult to design assays and negatively affect how the compound behaves in vivo. Therefore, inadequate solubility may prove to be a barrier to therapeutic development. In general, drug solubility is influenced by several factors such as lattice energy, molecular arrangement, bond strength, weak bonding forces, lipophilicity, ionisation potential, pH, cosolvency, additives, dielectric constant, solubilisation by surfactant, hydrotrophy, complexation, temperature, pressure, and molecular volume. If these factors have been studied well during preformulation studies, they can be useful for final formulation development with fewer chances of drug failure [51].

In summary, the variables that might alter a drug's solubility profile include the temperature, pH conditions, diluents, additives, solvent system, and the physical condition of drug molecules. The common ion releases in the medium in presence of


**Table 4.**

*BCS classification system for solubility and permeability.*

solubilising agents responsible for drug molecules crystallisation [52, 53]. Solubility, particularly water solubility, is a crucial physical-chemical property of a medicinal ingredient. For a medication to be therapeutically effective in the physiological pH range of 1–8, considerable water solubility is required.

If a drug substance's solubility is less than ideal, consideration must be paid to increasing it. 10 mg/ml is considered as poor solubility which may result in irregular or partial drug absorption from 1 to 7 pH range at 37°C. But for novel molecules, an understanding of two fundamental qualities is necessary [14].
