Pre-Formulation Considerations in Drug Development

Pre-formulation Considerations

Chapter 4 Lecture Objectives

• Demonstrate the science of preformulation.

• Familiar with the physical-chemical properties that to be investigated during preformulation.

Preformulation

• Definition: The investigation of physical and chemical properties of a new drug substance alone or in combination with other excipients.

• Purpose: Preformulation is a phase of the research & development process where research scientists characterize the physical, chemical, and mechanical aspects of a new drug under investigation in order to develop a stable, safe, and effective dosage form for clinical use.

Drug Research and Development Procedure

• Stages of Drug Development:

  • Drug screening

  • Leading API identification

  • Leading API optimization

  • Clinical Studies

  • GMP Manufacturing

Objective of Preformulation

• To formulate stable and effective dosage forms

• To increase drug stability

• To improve drug bioavailability

• To reduce drug-excipient incompatibility

Physical Properties

• Definition: Physical properties include physical description, particle size, crystalline structure, melting point, and solubility.

Physical Description

• Types of Drug Forms:

  • Drugs can be used therapeutically as solids, liquids, and gases.

  • Liquid drugs are used much less than solid drugs; gases, even less frequently.

Problems for Liquid Drugs

• Volatility: Many liquids are volatile and must be physically sealed from the atmosphere to prevent evaporation loss.

• Dosage Form Formulation:

  • Liquid drugs that are intended for oral administration cannot generally be formulated into tablet form without chemical modification.

  • Liquid drugs may be developed into a solid ester or salt form that will be suitable for tablets or drug capsules.

  • Mixing liquid drugs with a solid or melted semi-solid material can improve formulation.

• Advantages:

  • For certain liquid drugs, especially those taken orally in large doses.

  • For drugs applied topically.

• Stability: Formulation and stability difficulties arise less frequently with solid dosage forms than liquid preparations.

• Market Trends: Many new drugs first reach the market as tablets or dry-filled capsules, later followed by liquid forms when pharmaceutical challenges are resolved.

• Survey Results:

  • Most physicians and patients prefer small, generally tasteless, accurately dosed tablets or capsules over analogous liquid forms.

  • Tablets and capsules constitute around 70% of dosage forms, with tablets dispensed twice as frequently as capsules.

Physical Property Characterization

• Microscopic Examination:

  • Provides information regarding particle size, size range, and crystal structure of raw material.

  • Solid drug powders must flow freely and not become entangled during processing.

  • Spherical and oval powders flow more easily than needle-shaped powders.

Heat of Vaporization

• Definition: The amount of heat absorbed when 1 g of drug substance vaporizes.

• Importance: Vapor pressure is critical in the operation of implantable pumps and in aerosol dosage forms.

• Clinical Application: For nasal inhalants treating nasal congestion, the required quantity of drug for effectiveness and duration can be determined by vapor pressure.

• Molecular Movement:

  • In liquids, molecules escape into a gaseous environment; in solids, molecules transition into vapor (e.g., sublimation of aspirin or ibuprofen).

• Safety Note: Smaller particle size correlates with greater vapor pressure, highlighting the need for personal protective equipment (PPE) for working with micronized hazardous powders.

Purity

• Definition: The percentage of a specified compound or element in an impure sample, usually expressed as % (m/m) or (W/W).

• Impact of Impurities:

  • Affect drug stability (may cause unexpected reactions).

  • May be toxic.

  • Affect the appearance of dosage forms.

• Detection of Impurities Methods:

  • Melting point measurement.

  • Thermal analysis.

  • Chromatographic techniques.

Melting Point

• Definition: The melting point or freezing point of a pure crystalline solid is defined as the temperature at which the pure liquid and solid exist in equilibrium.

• Significance: An altered melting point or range can indicate contamination or impurities in a drug.

• Processing Consideration: Drugs with low melting points may soften during processing steps that generate heat, such as particle size reduction or compression.

• Equipment Used: Hot stage microscopy.

Melting Point Depression

• Definition: The phenomenon where the melting point of material decreases with reduction in size.

• Specific Context: This phenomenon is prominent in nanoscale materials, which melt at temperatures lower than their bulk form.

Thermal Analysis Techniques

Differential Scanning Calorimeters (DSC)

• Measurement: DSC measures temperatures and heat flows associated with thermal transitions in materials.

Thermo Gravimetric Analysis (TGA)

• Measurement: TGA measures weight changes in a material as a function of temperature or time under a controlled atmosphere. Useful for detecting impurities like water or residual solvents.

Chromatography

• Preparatory Phases:

  • Preparation of stationary phase & mobile phase.

  • Mobile phase runs in both sample & standard substance.

• Types of Chromatography:

  • Thin layer chromatography (TLC)

  • High Performance Liquid Chromatography (HPLC) (used for identifying organic related impurities).

Particle Size and Its Effects

• Impact of Particle Size: Most physical and chemical properties of drug substances are affected by particle size, including:

  • Dissolution rate

  • Bioavailability

  • Content uniformity

  • Taste, texture, color, stability

• Flow Characteristics and Sedimentation Rates: Also influenced by particle size.

Polymorphism

• Definition: Polymorphism is the ability of a solid material to exist in more than one crystalline form.

• Significance: This is critical for drug formulation. Different crystal forms exhibit varying physicochemical properties, such as melting point and solubility.

• Prevalence: At least one-third of organic compounds exhibit polymorphism.

• Comparison: Amorphous compounds tend to be more soluble than crystalline forms.

Incompatibility with Excipients

• Definition: Incompatibility arises when mixing substances creates undesirable products.

• Types of Incompatibility:

  • Physical: Changes to physical properties like solubility, appearance, miscibility (e.g., oil and water).

  • Chemical: Involves reactions such as reduction, oxidation, hydrolysis.

Solubility

• Importance: Solubility is a fundamental physicochemical property; most often referring to aqueous solubility needed for systemic absorption.

• Challenges: Poor solubility can lead to incomplete or erratic drug absorption.

Strategies for Increasing Solubility

• Methods:

  • Chemical modification (conversion to salt or ester forms).

  • Decrease particle size (micronization).

  • Adjust pH.

  • Adding cosolvents (such as dimethyl sulfoxide, ethanol, glycerin, PEG).

  • Form complex (e.g., cyclodextrin).

Dissolution Rate

• Definition: The time it takes for a drug to dissolve in a fluid.

• Impact on Pharmacokinetics: If dissolution is the rate-limiting step, anything affecting it will influence absorption.

• Strategies to Increase Dissolution Rate:

  • Decrease particle size of the drug.

  • Using a highly water-soluble salt of the parent substance.

Product Stability

Lecture Objectives

• Demonstrate the science of drug stability.

• Compare physical instability versus chemical instability.

• Know the approaches for preventing different mechanisms of instabilities.

Importance of Stability

• Definition: A pharmaceutical product must maintain an elegant and professional appearance, uniformity of dose, and active ingredient availability throughout the expected shelf life.

• Risks of Instability:

  • Decrease in therapeutic activity.

  • Degradation may produce toxic substances.

  • Physical changes (e.g., caking, disintegration).

Definitions of Stability

• Chemical Stability: Each active ingredient retains its chemical integrity and labeled potency over time and is uniform from dose to dose.

• Physical Stability: Retention of original physical properties, including appearance, dissolution, and uniformity.

• Microbiological Stability:

  • Sterile products remain sterile, non-sterile products remain free of objectionable microorganisms.

  • Effectiveness of preservatives must be maintained.

• Therapeutic Stability: Therapeutic effects remain unchanged.

• Toxicological Stability: No significant increase in toxicity occurs over time.

Chemical Instability: Hydrolysis

• Overview: Hydrolysis is one of the most common destructive processes for drugs, involving the interaction of drug molecules with water.

• Example:

  • Reaction: Aspirin + H2O → salicylic acid + acetic acid.

• Inhibition Strategies:

  • Decrease water content.

  • Reduce product’s exposure to environmental conditions.

  • Control pH of solutions.

Chemical Instability: Photolysis

• Definition: Decomposition of compounds as a result of light exposure.

• Example: Sodium nitroprusside: stable for 1 year if protected from light, but only 4 hours if exposed to room light.

• Prevention:

  • Use amber containers.

  • Wrapping in cardboard or aluminum foil.

Physical Instability Pathways

• Polymorphism: Can cause variations in solubility, compressibility, and melting points.

• Crystallization: Alters particle size distribution in suspensions, often caused by temperature changes.

• Precipitation: Formation of solid precipitates from a solution.

• Vaporization: Loss of solvent, increasing concentration.

• Adsorption: Loss of active ingredients to containers and equipment.

Stability Factors

Temperature

• Role of Temperature: Increased heat accelerates chemical reaction rates.

• Arrhenius Equation: $k = A e^{-E<em>a/RT}$ (where k = reaction rate constant, A = pre-exponential factor, Ea = activation energy, R = gas constant, T = temperature).

pH

• Influence of pH: Reaction rates vary significantly with pH.

• Application: pH versus rate of degradation plots help determine optimal formulation pH to maximize stability.

Light

• Impact of Light: Light can catalyze chemical reactions, influencing stability.

• Minimization Strategies: Use protective packaging such as amber glass or opaque containers.

Air

• Role of Oxygen: Oxygen exposure can induce degradation via oxidation.

• Control Mechanisms:

  • Tightly seal containers.

  • Purge air with nitrogen, and incorporate antioxidants into formulations.

Solvent Effects

• Challenges of Solvent: Some drugs may be unstable in certain solvents; reactions can vary with solvent dielectric constants.

• Mitigation: Prepare drugs in suspension and reconstitute immediately before use.

Particle Size

• Impact of Particle Size: Smaller particles have increased reactivity due to enhanced surface area.

• Considerations: Smaller particles dissolve and disperse better but may affect overall stability and release rates.

Ionic Strength

• Definition: Concentration of electrolytes within formulations impacts reaction rates and stability.

• Implications: Ionic strength can significantly affect compatibility and stability of formulations.

Microbiological Stability

• Definition: Microbiological stability refers to the absence of contamination and fulfillment of sterility standards in formulations.

• Prevention: Achieved through preservatives and appropriate packaging.

Case Studies: Microbiological Contamination Risks

• Example: Methylprednisolone Acetate injections linked to a meningitis outbreak underscored the importance of microbiological stability.