Preformulation and Drug Stability

Lecture Objectives
• Demonstrate the science of preformulation.
• Familiar with the physical-chemical properties that to be
investigated during preformulation

Preformulation

Preformulation is the investigation of a new drug substance’s physical, chemical, and mechanical properties - alone and with excipients - to develop a dosage form that is stable, safe, and effective.

It occurs during drug development before clinical studies and GMP manufacturing.

Goals

• Increase drug stability

• Improve bioavailability

• Identify and reduce drug-excipient incompatibilities

• Select an appropriate and stable dosage form

Physical Properties

Important physical properties evaluated during preformulation include:

• Physical description

• Particle size

• Crystalline structure

• Melting point

• Solubility

Physical Description

Drugs may be used therapeutically as:

• Solids - most commonly used form

• Liquids - used less often than solids

• Gases - used least often

Solid vs. Liquid Drugs

Solid dosage forms are generally more stable and easier to formulate than liquids.

Problems with liquid drugs

• Many liquids are volatile, so they must be sealed from the atmosphere to prevent evaporation.

  • Example: vitamins A, D, and E may be enclosed in soft gelatin capsules.

• Liquids intended for oral use usually cannot be made into tablets without chemical modification.

  • A liquid drug may be converted into a solid ester or salt so it can be made into a tablet or capsule.

• A liquid drug can also be mixed with a solid or melted semisolid material.

Advantages of liquid dosage forms

Liquids may be useful:

• For drugs taken orally in large doses

• For drugs applied topically

Solid vs. liquid dosage forms

• Formulation and stability problems occur less often with solid dosage forms than with liquids.

• Many drugs are first marketed as tablets or dry-filled capsules; a liquid form may be developed later.

• Physicians and patients generally prefer small, tasteless, accurately dosed tablets or capsules over liquids.

• Tablets and capsules make up about 70% of dosage forms.

• Tablets are dispensed about twice as often as capsules.

Microscopic Examination

Microscopy provides information about:

• Particle size and size range

• Crystal structure

• Particle shape

Particle shape matters for powder flow:

• Spherical/oval particles flow more easily.

• Needle-shaped particles may entangle and flow poorly.

Heat of Vaporization and Vapor Pressure

Heat of vaporization: heat absorbed when 1 g of a substance vaporizes.

Vapor pressure is important for:

• Aerosol dosage forms

• Implantable drug pumps

• Nasal inhalants

• Worker safety with micronized hazardous powders

Smaller particles have greater vapor pressure because of their larger surface area.

Purity

Purity is the percentage of the desired compound in a sample, usually expressed as % (m/m) or (w/w).

Impurities can:

• Decrease stability( cause unexpected reactions)

• Be toxic

• Alter appearance

Methods to detect impurities:

• Melting point measurement

• Thermal analysis

• Chromatographic technique

Melting Point

The melting point of a pure crystalline solid is the temperature where pure solid and liquid forms exist in equilibrium.

Why it matters:

• Helps assess purity

• A shifted or altered melting peak can indicate contamination

• Low-melting drugs may soften during milling, compression, or other heat-generating processes

Melting-point depression: smaller particles, especially nanoscale particles, may melt at a lower temperature than bulk material. This is usually not important for most formulations.

Thermal Analysis

• DSC (Differential Scanning Calorimetry): measures heat flow and temperature changes during thermal transitions.

• TGA (Thermogravimetric Analysis): measures weight changes as temperature/time changes; useful for detecting water or residual solvents.

Chromatography

Chromatography is used to detect and analyze organic-related impurities in a drug sample.

Basic process

• Prepare the stationary phase and mobile phase.

• Run the mobile phase with both the sample and a standard substance.

• Compare the results to identify impurities.

Types

• Thin-layer chromatography (TLC)

• High-performance liquid chromatography (HPLC)

Particle Size

Particle size affects:

• Dissolution rate

• Bioavailability

• Content uniformity

• Taste and texture

• Color

• Stability

• Powder flow

• Sedimentation rate

Polymorphism

Polymorphism is the ability of a solid to exist in more than one crystal structure.

Different polymorphs may have different:

• Melting points

• Solubilities

• Compressibility

• Bioavailability

• Chemical and physical stability

A drug may also exist in an amorphous (noncrystalline) form. Amorphous forms are generally more soluble than crystalline forms.

Methods to evaluate crystal form:

• Hot-stage microscopy

• DSC

• Infrared spectroscopy

• X-ray diffraction (XRD)

Drug-Excipient Incompatibility

An incompatibility occurs when substances are mixed and form an undesirable product.

olubility

A drug must be in solution before it can enter systemic circulation and produce an effect.

Poor solubility can cause incomplete or unpredictable absorption.

Ways to increase solubility:

• Convert drug to a salt or ester

• Decrease particle size (micronization)

• Adjust pH

• Add cosolvents, such as DMSO, ethanol, glycerin, or PEG

• Form complexes, such as cyclodextrin complexes

For weak acids and weak bases, solubility is pH-dependent and can be estimated using the Henderson-Hasselbalch equation.

Dissolution

Dissolution rate is the time it takes for the drug to dissolve in fluid.

If dissolution is the rate-limiting step, it controls absorption and can affect:

• Onset of action

• Intensity of response

• Duration of response

• Overall bioavailability

To increase dissolution rate:

• Decrease particle size

• Use a highly water-soluble salt of the parent drug

Drug Stability

A stable pharmaceutical product should remain elegant in appearance, maintain dose uniformity, and provide active drug throughout its shelf life.

Why Stability Matters

Instability can cause:

• Loss of therapeutic activity

• Toxic degradation products

• Settling/caking in suspensions

• Creaming or phase separation in emulsions

• Tablet hardening or softening

• Discoloration

Types of Stability

Chemical Instability

Chemical Instability: Oxidation

Oxidation is a chemical degradation process involving the loss of an electron, which causes an increase in positive valence.

Mechanism

• Oxidation often occurs as a chain reaction.

• Oxygen reacts with a drug molecule, forming a highly reactive free radical.

• The free radical then attacks nearby drug molecules, causing further degradation.

Drug Groups Susceptible to Oxidation

• Aldehydes

• Alcohols

• Phenols

  • Example: dopamine → dopamine o-quinone

• Sugars

• Alkaloids

• Unsaturated fats and oils

Prevention

• Add antioxidants to inhibit oxidation.

• Add chelating agents to bind metal ions that may promote oxidation.

• Protect products from light, since light can speed up oxidative reactions.

Hydrolysis

Hydrolysis is drug breakdown caused by reaction with water. It is one of the most common drug-degradation pathways.

Example: aspirin + water → salicylic acid + acetic acid.

Drugs especially susceptible include those containing:

• Esters

• Amides

• Lactones

• Lactams

How to reduce hydrolysis:

• Decrease water in the product

• Limit environmental exposure

• Control solution pH

Photolysis

Photolysis is decomposition caused by light.

Prevention:

• Amber-colored containers

• Cardboard outer packaging

• Aluminum foil overwraps

Example: sodium nitroprusside is stable much longer when protected from light.

Chemical Instability Other Pathways

Decarboxylation

Decarboxylation is the loss of a carboxyl group (-COOH) from a drug molecule.

• Produces a hydrocarbon (R-H) and carbon dioxide (CO₂).

Racemization

Racemization is the conversion of one stereoisomer into its mirror-image form.

• Example: L-serine ↔ D-serine

• This can alter drug activity because the body and drug targets may respond differently to each stereoisomer.

Physical Instability

Major pathways include:

• Polymorphic conversion: changes solubility, compressibility, and melting point

• Crystallization: changes particle-size distribution in suspensions; often caused by temperature fluctuations

• Precipitation: formation of solid particles from solution

• Vaporization: solvent loss, causing increased concentration; more likely at higher temperature

• Adsorption: drug sticks to containers, filters, tubing, or syringes - especially important for low-dose drugs

Physical Instability: Pathways

Protein Denaturation

Protein denaturation is when a protein loses its normal 3D shape and biological activity because of physical or chemical stress.

Examples: denaturations, aggregation, surface absorption, precipitation.

Causes can be changes in:

• Changes in pH

• Temperature

• Agitation

• Shearing forces

Other Stablility Factors:

• Temperature

• pH

• Light

• Air

• Humidity

• Solvent

• Particle Size

• Ionic Strength

Why Temperature? Reaction Rate: Arrhenius Equation

\[ k = Ae^{-E_a/RT} \]

• k = reaction rate constant

• A = frequency factor

• Eₐ = activation energy

• R = gas constant

• T = temperature

Key Idea

As temperature increases, the reaction rate constant (k) increases, so the chemical reaction happens faster.

\[ T \uparrow \rightarrow \frac{E_a}{RT} \downarrow \rightarrow k \uparrow \]

Study takeaway: Higher temperature can speed up drug degradation, reducing stability and shelf life.

pH

Specific acid catalysis: a reaction is sped up specifically by H⁺ (hydrogen) or H₃O⁺ (hydronium) ions.

Specific base catalysis: a reaction is sped up specifically by OH⁻ (hydroxide) ions.

Why pH Matters

• pH reflects the concentration of H⁺ ions.

• Changing pH changes the concentration of H⁺ and OH⁻.

• Therefore, changing pH can change the reaction rate and drug stability.

\[ \text{Change in pH} \rightarrow \text{change in } [H^+] \text{ or } [OH^-] \rightarrow \text{change in degradation rate} \]

Acid- and base-catalyzed reactions can strongly affect degradation rate.

• Degradation-rate-vs.-pH curves help identify the optimum pH for maximum stability.

• pH control is particularly important for hydrolysis reactions.

Light

Light can increase the rate of some chemical reactions, acting as a catalyst.

Use protective packaging, such as amber glass or amber plastic containers.

Why Does Air Matter?

Air can affect drug stability because it contains oxygen and carbon dioxide (CO₂).

• Oxygen can cause drug degradation by oxidation.

• CO₂ can form insoluble carbonates in solid dosage forms.

  • This can decrease tablet disintegration and dissolution.

How to Minimize Air Exposure

• Package products in tightly closed containers.

• Fill containers as full as possible to reduce air space.

• Purge air from containers with nitrogen.

• Add antioxidants to prevent oxidation.

Why Does Humidity Matter?

High humidity can decrease drug stability by adding moisture to the formulation.

Effects of Humidity

• Causes hydrolysis of water-sensitive drugs.

• Can speed up degradation reactions with excipients.

• May cause physical changes, including:

  • Caking or clumping

  • Softening of tablets/capsules

  • Microbial growth

How to Reduce Humidity Effects

• Manufacture and store products in dry, low-humidity conditions.

• Add desiccants (such as silica gel) to packaging.

Why Does Solvent Matter?

Solvent effects can be complex and difficult to predict because some drugs are unstable in solution.

• The solvent’s dielectric constant can affect reaction rates.

  • Reactions involving oppositely charged ions are faster in solvents with a low dielectric constant.

  • Reactions involving similarly charged species are favored in solvents with a high dielectric constant.

To reduce solvent-related instability:

• Formulate the drug as a suspension.

• Reconstitute the drug immediately before dispensing.

Why Does Particle Size Matter?

Smaller particles have more surface area, making them more reactive and potentially less stable.

Particle size must be balanced with other formulation effects:

• Dissolution: smaller particles dissolve faster.

• Sedimentation: smaller particles remain suspended longer in suspensions and emulsions.

• Solubility: smaller particles tend to be more soluble.

Why Does Ionic Strength Matter?

Ionic strength is the concentration of electrolytes in a formulation.

• It can affect reaction rates.

• Its effect depends on the active ingredient, excipients, and solvent present.

Microbiological Stability

Microbiological stability means the formulation has not been affected by microorganisms and meets standards for:

• Lack of contamination

• Sterility, when required

Prevention

Microbiological contamination can be prevented by:

• Adding appropriate preservatives

• Using proper, protective containers