TB2: Preformulation and Solids

What’s the difference between Formulation and Preformulation?

Formulation - The process developing a drug candidate into a drug product.

Preformulation - The process of studying a drug’s properties (solubility, stability, and compatibility) before its made into a final product. *Helps in planning how to formulate the drug best.

What is the purpose of pre-formulation and its role in the development of medicines

Preformulation aims to generate useful information for dosage form of a drug that is:

• Stable

• Bioavailable (the extent/rate that the active ingredient in a drug is absorbed and reaches its target.)

• Mass production.

Describe the nature of the crystalline state

The crystalline state is a highly ordered solid form where molecules, atoms, or ions are arranged in a repeating three-dimensional pattern.

It has long-range order, a defined geometric shape, a sharp melting point, and anisotropic properties (varying physical properties in different directions).

Describe the nature of the forces bringing crystals together

Crystals are held together by intermolecular and intramolecular forces, which determine their stability, melting point, and solubility.

• Ionic

• Covalent

• Hydrogen

• Van der Waals

• Metallic bonds

Explain the meaning of the terms unit cell, crystal class, crystal form and crystal habit

Unit Cell: The smallest, repeating unit in a crystal lattice. The building block of the crystal.

Crystal Class: Crystals that share common symmetry properties. Classes such as cubic, tetragonal, or hexagonal.

• Influences the crystal’s shape and internal structure.

Crystal Form: External shape or appearance of a crystal. It is defined by the arrangement of crystal faces (flat surfaces), also focuses on internal symmetry and structure of the unit cell.

Crystal Habit: The appearance or shape of the crystal as it grows. Overall shape such as its tabular, prismatic, or needle-like.

Why are platelike crystals easier to inject through a fine needle than needle-like crystals?

Equidimensional crystals have better flow properties and compaction characteristics than needle-like crystals, making them more suitable for tableting.

What is crystallisation?

The process where a solid forms in an ordered, repeating pattern from a solution, melt, or gas.

It helps control the purity and stability of drugs.

What is Crystal Engineering?

The design of crystals to improve their properties, like solubility and stability.

This can be done by:

• Changing the crystal form

• Making co-crystals

• Forming salts to enhance drug performance

Name the two processes that control crystallisation

• Nucleation: Formation of crystal ‘embryos’ or ‘seeds’.

• Growth: Growth of crystals - molecules add to faces of ‘seeds’ from solution.

Describe how growth works for Crystal Engineering

Crystal grows by molecules adding to the faces of the crystal.

Different crystal faces can grow at different rates giving rise to a particular habit.

Habit is modified by changing the crystallization process commonly by adding impurities such as adding a surfactant to the solution.

Define Amorphous

Solids that consist of molecules arranged in a somewhat random manner - just like in a liquid state.

They tend to flow when subjected to sufficient pressure over a period of time.

This state is unstable compared to crystalline - due to high energy.

It does offer higher solubility and bioavailability but less stability.

Define Polymorphs

Crystals that contain the same molecular species, but have different unit cells.

Polymorphs have different properties:

• Melting Point

• Dissolution rate

• Apparent Solubility

The Importance of Polymorphism

• Medicines must be fully characterised and their properties must be predictable.

• Drugs that have polymorphic forms must be characterised and the medicine should contain ONE specific polymorph with the desired properties.

• Methods are required to separate different polymorphs or to make sure we can manufacture drugs polymorphically pure (i.e. containing only one crystal form).

How to identify Polymorphism?

Polymorphs have different unit cells, and interactions between molecules in the crystal are different.

They have different lattice enthalpies (the amount of energy released when the crystal forms from the vapour).

Many of their physical properties are different (X-ray diffraction, IR spectrum, Melting Point, Dissolution rate).

We can analyse solid drugs in these ways to see if there are different polymorphs present.

Describe Crystal Hydrates

Crystallisation from solution can cause solvent molecules to become trapped in the crystal.

• Hydrates: When water is the solvent

• Anhydrates: No water of crystallisation.

What is quicker to dissolve between Hydrate and Anhydrate crystals?

Anhydrous crystals dissolve faster than hydrated ones because they don’t have water stuck inside them.

This makes it easier for the liquid to break them apart.

Since hydrated crystals have water trapped in them, it takes longer for the liquid to dissolve them.

Define Pseudo-Polymorphism

When solvent molecules get trapped in the crystal structure of a solid, this creates a compound known as a solvate.

Solvates exist in different crystal forms, Pseudo-polymorphs.

Polymorphic Solvates: Water forms H-bonds between drug molecules, holding the crystal structure together.

These are stable and can change crystal structure when heated to remove the water.

Pseudo-polymorphic Solvates: Water fills the spaces in the crystal. When heated, the water can be removed easily, but the crystal structure stays the same.

Name techniques used to study crystal structures

• TGA: Thermal Gravimetric Analysis

• DSC: Differential Scanning Calorimetry

• XRD: X-Ray Diffraction