**3.2 Bulk properties and characterisation: physical, analytical, and physicochemical**

#### *3.2.1 Solid-state properties*

They include crystallisation, salt formation, polymorphisms, and solvates that profoundly impact solubility, stability, permeability, and finally bioavailability. These are the most crucial parameters of drugs that are necessary for the effective development of drug candidates for patients [36]. For example, powders are masses of solid particles encased in the air (or another fluid), these two systems are significantly bearing on the bulk properties of the powders. The fluid content and other variable parameters are associated with the powder formulations that may affect flow


#### **Table 2.**

*List of various organoleptic properties.*

performance which is impacted by the physical features of particles like shape, size, size inconsistency, angularity, and rigidity. Some outside factors including humidity, aeration, vibration, and conveying environment intensify the problem [37].

#### *3.2.2 Flow properties*

The flow characteristics of powders are essential to successful tabletting operations. For effective mixing and tolerable weight consistency for the compressed tablets, an optimum flow of granules/powders is required. Suppose, at the preformulation stage a drug is categorised as "poor flowable" therefore the proper selection of excipients can resolve this problem. Precompression and granulation methods are utilised for powder drugs to improve their flow behaviour. A preformulation test of the granule mass for the measurement of flow properties is performed with the help of the angle of repose, flow through an orifice, Hausner ratio, bulk and tapped density, inter-particle porosity, Carr's index and ideal flowability. Generally, a uniform shape or large crystal displays a narrower angle of repose and a low Carr's index resulting from changes in particle size and shape [38].

The angle of repose can be understood as the maximum angle formed between the free-standing surface of the powder heap and the horizontal plane of the powder at the base. It may use to evaluate the interparticle force of powder particles and bulk characterisation of solids.

The range of angle of repose can vary from 0° to 90°, the angle of repose value below 25° represents excellent flow properties however, on the other if the angle of repose value ranges between 25° and 45°, the flow is considered poor, the values of angle of repose indicated in **Table 3**. The formula for the calculation of the angle of repose is as follows [39].

$$\text{AOR} : \tan \theta^{-1} \left( \text{2h/d} \right) \tag{1}$$

h is heap height, and d is the horizontal base diameter.


*Vo: volume, M: known weight of the granule's mixture, Vt: tapped volume in measuring cylinder, Pb: bulk density, Pt: tapped density, AOR: angle of repose*

#### **Table 3.**

*Preformulation tests for measurement of granule flow properties.*

#### *3.2.3 Particle size distribution*

The particle size of dosage form affects the physicochemical properties and biopharmaceutical behaviour of drug substances. Drug solubility is frequently inversely proportional to the particle size; for example, a smaller particle size dosage form has a large surface area, similarly surface area to volume ratio as well. A stronger contact between the surface area and the solvent increases the solubility. Particle size reduction methods like milling and grinding frequently subject the drug product to high levels of physical stress, which could lead to degradation [43]. Moreover, micronization is the conventional technique used to make particles smaller and increase the surface area of drugs thereby enhancing solubility and dissolution.

However, micronization milling techniques (rotor-stator colloid mill, and jet mill) are not appropriate for drugs because they do not change the saturation solubility.

Griseofulvin, progesterone, phenacetin, and fenofibrate are examples where smaller particle with large surface area enhances drug bioavailable concentration [44]. Spray drying, active compound milling, and grinding are common methods of particle size reduction. These techniques frequently subject the therapeutic product to severe physical stress, which could lead to degradation.

#### *3.2.4 Compressibility*

Compressibility is the ability of drug powders to decrease in volume under pressure and compress into tablet dosage forms with specific tensile strength. It is calculated by the Hausner ratio and Carr's index (formula mentioned in **Table 3**) to determine the flow behaviour of powder-based drugs to calculate the density at the preformulation stages [45].
