Seminar on

Preformulation Study of Liquid Orals

By :

Shrikant Sharma
1st year, M. Pharm.

Submitted to: HOD Department of Pharmaceutics

CONTENTS i. Particle Properties i. ii. iii. ii. Particle Shape Particle Size Size Distribution

Surface Properties and Interfacial Phenomena i. ii. iii. iv. v. The Interface Particle Interactions Electrical Properties of the Interfaces Wetting Adsorption

iii

Instabilities and Stabilization Concepts i. ii. Instabilities Stabilization by Electrostatic Repulsion

iii. Stabilization by Steric Repulsion

vi

Rheological Properties
i. ii. Newtons Law and Newtonian Flow Pseudoplastic Flow

iii.
iv. v.

Plastic Flow
Dilatant Flow Thixotropy and Rheopexy

vii
viii ix

Solubility
pH Temperature

Particle Properties
Applicable for Disperse System The mean particle diameter as well as the particle size distribution of the dispersed phase have a profound effect on the properties of the dosage forms, such as product appearance, settling rate, drug solubility, resuspendability, and stability. Can also affect the drug release from the dosage forms that are administered orally, parenterally, rectally, and topically.

Particle Shape
Insoluble particles of drugs obtained from various sources and manufacturing processes are seldom uniform spheres even after size reduction and classification. Their aggregation behavior produces an even greater variety of shapes and structures. The information on particle shape is particularly important for the understanding of the behavior of suspensions during storage. The particle shape of the suspended particles (suspensoids) may have an impact on the packing of sediment (e.g., packing density and settling characteristics), and thus products resuspendability and stability.

The viscosity of colloidal dispersions is affected by the shape of the dispersed phases.
Spherocolloids form dispersions of relatively low viscosity, while systems containing linear particles are generally more viscous.

Particle Size and Size Distribution

The particle size can significantly affect the absorption behavior of a drug. Certain types of dosage forms require specific size ranges; for example, suspension aerosols delivering drugs into the respiratory tract should contain particles in the order of 0.5 to 5 mm and no particles larger than 10 mm. Particle weight data may be more useful in sedimentation studies, whereas Particle number data are of particular value in surfacerelated phenomena such as dissolution.

Surface Properties and Interfacial Phenomena

One of the most obvious properties of a disperse system is the vast interfacial area that exists between the dispersed phase and the dispersion medium. When considering the surface and interfacial properties of the dispersed particles, two factors must be taken into account: increase in the surface free energy as the particle size is reduced and the specific surface increased presence of an electrical charge on the particle surface.

The Interface An interface is defined as a boundary between two phases. The solid-liquid and the liquid-liquid interfaces are of primary interest in suspensions and emulsions, respectively. A large surface area of the dispersed particles is associated with a high surface free energy that renders the system thermodynamically unstable. The surface free energy, G, can be calculated from the total surface area, A, as follows

Particle Interactions
The interactions between similar particles, dissimilar particles, and the dispersion medium constitute a complex but essential part of dispersion technology. Such interparticle interactions include both attractive and repulsive forces. As the particles approach one another, both attractive and repulsive forces are operative. If the attractive forces prevail, agglomerates result, indicating an instability in the system. If repulsive forces dominate, a homogeneously dispersed or stable dispersion remains. Various types of attractive interactions are operating: (i) dipole-dipole or Keesom orientation forces, (ii) dipole-induced dipole or Debye induction forces, (iii) Induced dipole-induced dipole or London dispersion forces, and (iv) electrostatic forces between charged particles.

Electrical Properties of the Interfaces

Most insoluble materials, either solids or liquids, develop a surface charge when dispersed within an aqueous medium.

Surface charges of particles may arise from several mechanisms like . the ionization of functional groups present at the surface of the particle adsorption or desorption of protons. Derjaguin, Landau, Verwey, and Overbeek developed a theory giving insight into the energy of interaction between suspended particles.
This theory is thus often referred to as the DLVO theory. It relates the stability of a disperse system to the electrolyte content in the continuous phase and provides an insight into the factors responsible for controlling the rate at which particles in disperse systems come into contact or aggregate.

Wetting
The wetting process is a concern particularly in the preparation of a liquid disperse system in which the internal phase is a solid.

A solid material to be suspended must first be separated into single particles, and the particles must be individually wetted by the dispersion medium to achieve a homogeneous distribution of the internal phase.
Experimentally, the degree of wetting of a powder can be evaluated by observing the contact angle, , which is defined by the boundaries of the solid surface and the tangent to the curvature of the liquid drop. 00 - Complete wetting 00 - 900 - Partial wetting 1800 - Unwettable

Adsorption
Adsorption is the tendency of atoms, molecules, ions, etc. to locate at a particular surface/ interface in a concentration that is different from the concentrations in the surrounding bulk media. Occurs as a result of the unequal distribution of the forces at the interfaces. Adsorption is termed positive if the concentration of adsorbed species at the interface is greater than that in the bulk, and negative when the opposite is true. Divided into two main classes Physical adsorption or physisorption Chemisorption Of special interest in liquid dispersions are the surface-active agents. Surfactants can arrange themselves to form a coherent film surrounding the dispersed droplets (in emulsions) or suspended particles (in suspensions).

Instabilities and Stabilization Concepts

The content uniformity and long-term stability of a pharmaceutical product are required for a consistent and accurate dosing.

Instabilities Instability of a dispersion may result from the tendency of the system to reduce its surface free energy Various Instabilities Flocculation sedimentation creaming coalescence

Stabilization
A disperse system remains stable as long as the repulsive forces are sufficiently strong to outweigh the van der Waals and/or other attractive forces. These repulsive forces are generally acquired through one or more of the following mechanisms: (i) Electrostatic repulsion, which arises from the presence of an ionic charge on the surface of the dispersed particles and

(ii) Steric repulsion, which arises from the presence of uncharged molecules on the surface of the particles.

Stabilization by Electrostatic Repulsion The electrostatic repulsive forces can prevent the dispersed particles having surface charges of the same sign from approaching each other, thus stabilizing the dispersion against interparticle attraction or coagulation. The addition of ions that are adsorbed onto the surface of the dispersed particles generally creates strong repulsion forces between suspended particles and stabilizes the system

Stabilization by Steric Repulsion

A strongly hydrated hydrophilic polymer is adsorbed onto the surface of a hydrophobic solid particle surrounded by an aqueous medium, so that the affinity of the polymer for water can exceed the attractive forces between the suspended particles. Adsorption of nonionic polymers (e.g., gums or water-soluble cellulosic derivatives) or surfactants (e.g., polysorbate 80) of sufficient chain length can create steric hindrance between adjacent particles.

Rheological Properties Rheology is the study of flow and deformation of materials under the influence of external forces. Flow properties important, especially for topical products. Consider a liquid material that is subjected to a shearing force. The liquid is assumed to consist of a series of parallel layers with the surface area A, the bottom layer being fixed. When a force is applied on the top layer, the top plane moves at a constant velocity, whereas each lower layer moves with a velocity directly proportional to its distance from the stationary bottom layer. The velocity gradient (dv/dr, the difference in velocity, dv, between the top and bottom planes of liquid separated by the distance, dr) is also called the rate of shear G = dv
dr

The rate of shear, G, is directly proportional to the shear stress, F`

 Newtonian Flow Newtonian fluids (e.g., pure water), a plot of rate of shear against shear stress gives a straight line, thus the slope (Z) is constant. Pseudoplastic Flow Many fluids show a decrease in viscosity with increasing shear rate. This behavior is referred to as shear thinning, which means that the resistance of the material to flow decreases and the energy required to sustain flow at high shear rates is reduced. These materials are called pseudoplastic Pseudoplastic flow can be found in emulsions, suspensions, as well as various pharmaceutical thickening agents, for example, polymer solutions. Plastic Flow Plastic fluids are Newtonian or pseudoplastic liquids, which exhibit a yield value At rest, they behave like a solid because of their interparticle association. The external force has to overcome these attractive forces between the particles and disrupt the structure. Beyond this point, the material changes its behavior from that of a solid to that of a liquid. Plastic flow is often observed in flocculated suspensions.

 Dilatant Flow In some cases, the viscosity increases with increasing shear rate. The system appears to become more structured and more viscous with increasing shear stress. This flow behavior is called dilatant Examples include pastes containing plasticizers, ionic polymers, suspensions with high solids content, highly pigmented systems. Thixotropy and Rheopexy It is defined as a reversible, time-dependent decrease in viscosity at a constant shear rate. The mechanism of thixotropy is the breakdown and re-forming of the gel structure. The rearrangement of particle is slow after removal shear stress, such as in many organic solvent-based systems, it may take longer for the fluid to regain its initial properties after shearing, and therefore the downcurve will be above the upcurve.

Solubility A key physicochemical property is solubility, particularly in aqueous media. Solution formation from separate solute and solvent phases must be thermodynamically favorable to occur spontaneously. A primary driving force for solution formation is entropy, which is a measure of the disorder brought about by mixing solute and solvent molecules.

Solution formation occurs at the solute-solvent interface

Various techniques can be used for increasing the solubility of the compound. 1. pH changes 2. Addition of surfactant 3. Cosolvency 4. Temperature changes 5. Complexation

pH pH may be defined as negative logarithm of hydrogen ion concentration APPLICATION OF pH 1. Enhancing the solubility Sodium salicylate ppt as salicylic acid when acidified 2. Increasing stability Vitamins are stable only with in a narrow pH range 3. Improving purity Insulin ppt from aqueous solution between pH 5.0 and 6.0 4. Optimizing biological activity Pepsin as maximum activity at pH 1.5 5. Comforting the body 6. Storage of product:

Temperature
Biphasic liquid dosage forms are thermodynamically unstable. Slight change in the temperature may cause instability in the dosage form. Elevated temperature may cause cracking, creaming, coalescence, phase inversion etc Single phase liquid dosage form may be thermodynamically stable (aqueous preparations).

References : Alexander T. Florence & Juergen Siepmann; Modern Pharmaceutics - Basic Principles and Systems; Volume 1; Informa Healthcare; Pg no. 357 421 Leon Lachman, H.A.Lieberman; The Theory and Practice of Industrial Pharmacy; 3rd edition; Varghese Publishing House; Pg no. 457 533 & 171 196

. Thank you