Introduction to Preformulation in Pharmacy

Introduction to Preformulation

• It's a critical phase where the physical and chemical properties of a drug molecule are determined.
• This stage ensures the development of a safe, stable, and effective dosage form.
• Preformulation starts when an experimental drug shows promise in animal studies, leading to human trials.
• It's the first step in rationally designing a safe and effective dosage form for a drug.

Goals and Objectives

• Aims to generate information for the formulation of the most stable and bioavailable dosage form.
• Establishing key physicochemical parameters of a new drug substance is crucial for a safe, stable, and efficacious dosage form.
• Determine the kinetic rate profile of the drug, establishing its physical characteristics.
• Assess compatibility with common excipients used in formulation.
• Understand how to process and store drug products to maintain their quality.
• Develop an optimal drug delivery system for the specific drug.

Physico-Chemical Characterisation

A. Physical Properties of Drug Substances

• These properties affect the structure, stability, and bioavailability of formulations.
• There are three categories influencing dosage form design:
  • Organoleptic Characterisation - This evaluates drug characteristics like colour, odour, texture, and taste.
  • Bulk Characterisation - Focuses on solid-state properties which may change during process development. Variations in these properties can impact drug development.
  • Solubility Profile - Determines how well the drug dissolves in different solvents, crucial for formulation development.

B. Chemical Properties of Drug Substances

• Important for understanding how a drug molecule changes over time and in different environments.
• Key chemical properties include:
  • Hydrolysis - Breakdown of the drug molecule by water.
  • Oxidation - Gain of oxygen, altering the drug's structure.
  • Reduction - Loss of oxygen, impacting the drug's stability.
  • Racemisation - Conversion of a chiral drug molecule to its mirror image, potentially affecting its activity.
  • Polymerisation - Formation of large molecules from smaller units, altering the drug's properties.

A. Physical Properties of Drug Substances

• These properties significantly influence dosage form design and drug performance.

i) Organoleptic Characterisation

• Evaluating a drug's sensory properties like colour, odour, texture, and taste.
• Aims for an aesthetically pleasing product.
• Colour should be appealing, and odour and taste should be pleasant.
• The absence of impurities is crucial, ensuring the drug is in its purest form.

ii) Bulk Characterisation

• Examining solid-state properties of drug molecules that may change during development.
• These properties are crucial for many subsequent steps in drug development.

Bulk Characterisation Includes:

• Crystallinity, Amorphism, and Polymorphism: Different solid-state forms of a drug.
• Fine Particle Characterisation: Analyzing particle size and shape.
• Density of Drug Substances: Determining the mass per unit volume.
• Powder Flow Properties: Assessing how easily the drug powder flows.

1. Crystallinity

• Crystalline compounds have a repetitive arrangement of atoms or molecules, forming distinct structures.
• Crystals can have different shapes, impacting their bulk and flow properties as well as chemical stability.
• Crystal habit refers to the external appearance of a crystal, while internal structure refers to the molecular arrangement within the solid.
• Crystallinity affects hardness, density, transparency, and diffusion, impacting drug absorption.
• Crystalline compounds might have stoichiometric or non-stoichiometric adducts, where the non-stoichiometric form is less desirable.

2. Amorphism

• Amorphous compounds have randomly placed atoms or molecules lacking a regular structure.
• Some drugs exist in an amorphous state, commonly prepared by rapid precipitation or lyophilization.
• Amorphous forms represent a higher energy state than the crystalline form, making them less stable.
• Amorphous forms are more soluble than crystalline forms, but this is a double-edged sword:
  • Increased solubility leads to better absorption.
  • They are less stable and tend to revert to more stable crystalline forms.

3. Polymorphism

• Polymorphism occurs when a substance exists in more than one crystalline form.
• The different forms are called polymorphs.
• Polymorphs can be:
  • Enantiotropic: Reversible changes between forms by adjusting temperature or pressure.
  • Monotropic: Only one form is stable at a given temperature and pressure.
• Different polymorphs can have different physical properties like melting point, solubility, and bioavailability, significantly impacting formulation development.

Fine Particle Characterisation

• Characterising the size and shape of drug particles has a major impact on bioavailability, dissolution rate, and formulation stability.
• Key aspects include:
  • Particle size distribution
  • Shape and surface area
  • Micromeritics - Study of the flow properties of powders.

Density of Drug Substances

• Bulk Density - Measured by pouring a sample of powder into a graduated cylinder and measuring the volume occupied.
• Tapped Density - Measured after the sample has been tapped repeatedly to remove air spaces.
• True Density - Determines the density of the solid material itself.
• Density affects packaging, flow properties, and the amount of drug in a given volume.

Powder Flow Properties

• Crucial for determining how well the drug powder flows during manufacturing.
• Factors influencing flow:
  • Particle size and shape
  • Surface area
  • Angle of repose - Natural inclination of the powder to form a pile.
  • Carr's Index - Ratio of tapped density to bulk density.
  • Hausner Ratio - Ratio of tapped density to bulk density.
• Poor flow properties can lead to issues during formulation, such as uneven dosage and clogging of machinery.

Solubility Profile

• Determining how well a drug dissolves in different solvents.
• Solubility is crucial for:
  • Absorption of the drug
  • Development of effective dosage forms
  • Stability of the formulation
• Factors influencing solubility:
  • pH - Acidity or alkalinity of the surrounding environment.
  • Temperature - Higher temperatures often improve solubility.
  • Presence of other substances - Salt formation, complexation, or co-solvents can impact solubility.
• Methods for improving solubility:
  • Salt formation - Converting the drug to a salt form.
  • Complexation - Forming a complex with another molecule.
  • Co-solvency - Using a mixture of solvents.
  • Micronization - Decreasing the size of drug particles.

B. Chemical Properties of Drug Substances

• Understanding these properties is essential for predicting and controlling the stability of a drug product over time.
• This knowledge allows for the design of formulations and packaging conditions that minimize degradation.

Hydrolysis

• Breakdown of a drug molecule by water.
• Hydrolysis occurs when water molecules interact with the drug molecule, breaking bonds and changing its structure.
• Factors affecting hydrolysis:
  • pH - Hydrolysis is often faster at extreme pH values outside the drug's optimal range.
  • Temperature - Higher temperatures increase hydrolysis rates.
  • Presence of other substances - Some ingredients can catalyze or inhibit hydrolysis.
  • Drug structure - Certain chemical groups are more susceptible to hydrolysis.

Oxidation

• The gain of oxygen, altering the structure of the drug molecule.
• Oxidation causes the drug molecule to become more reactive and unstable.
• Factors affecting oxidation:
  • Oxygen concentration - Higher oxygen concentration increases the rate of oxidation.
  • Metals - Certain metals can act as catalysts for oxidation.
  • Light - Ultraviolet (UV) light can accelerate oxidation.
  • Temperature - higher temperatures increase oxidation rates.

Reduction

• The loss of oxygen from a drug molecule, potentially affecting its activity and stability.
• Reduction can occur in the presence of reducing agents such as hydrogen.

Racemisation

• Conversion of a chiral drug molecule to its mirror image (enantiomer).
• Chiral drugs have two enantiomers - mirror images of the same molecule - that often have different pharmacological activities.
• Drug molecules can undergo racemisation due to heat, light, or pH changes.
• This can impact the effectiveness of the drug.

Polymerisation

• Joining of smaller molecules (monomers) to form larger molecules (polymers).
• Polymerisation can alter the drug's properties, making it less effective or even toxic.
• Factors influencing polymerisation:
  • Drug structure - Some drugs are more prone to polymerisation than others.
  • Temperature - Higher temperatures accelerate polymerisation.
  • Presence of catalysts - Some substances can speed up polymerisation.

Stability Considerations

• Preformulation studies provide valuable insight into the stability of a drug and its dosage form.
• This knowledge is essential for developing effective, safe, and marketable formulations.
• Stability is a crucial factor in determining the shelf life of a drug product.
• Factors impacting stability:
  • Chemical degradation - Breakdown of the drug molecule due to chemical reactions.
  • Physical instability - Changes in physical properties such as polymorphism, crystal growth, or particle size.
  • Microbial contamination - Growth of microorganisms in the drug product.
• Maintaining stability is achieved through:
  • Proper formulation design - Selecting excipients and processing methods to minimize degradation.
  • Suitable packaging - Using containers that protect the drug product from environmental factors.
  • Controlled storage conditions - Maintaining appropriate temperature, humidity, and light exposure.
• Preformulation studies provide the foundation for determining the best packaging and storage conditions to ensure the drug's stability over time.

Impact on Stability of Dosage Forms

Solid Dosage Forms

• Tablets: Preformulation studies help in selecting appropriate excipients to ensure the stability of the tablet during processing and storage.
• Capsules: Preformulation data helps in choosing appropriate capsule shells to ensure the drug's stability and protect it from environmental factors.

Liquid Dosage Forms

• Solutions: Studies help in finding solvents that maintain the drug's stability and prevent degradation.
• Suspensions: Preformulation findings help formulate stable suspensions with proper particle size and excipient selection to avoid sedimentation.

Parenterals

• Injections: Preformulation is crucial to ensure the drug's stability in the injection solution and its compatibility with the chosen injection device.

• Preformulation studies are critical for developing safe and effective dosage forms that maintain stability over time. Understanding the physical and chemical properties of a drug substance is fundamental for successful formulation development.

This quiz explores the critical phase of preformulation, where the physical and chemical properties of drug molecules are assessed to ensure their safety and efficacy. Gain insights into the goals and objectives of establishing optimal dosage forms, compatibility with excipients, and maintaining drug quality. Perfect for those studying pharmaceutical sciences.