Physical and Chemical Properties of Drugs

PHYSICAL AND CHEMICAL PROPERTIES OF DRUGS PHARMACEUTICS - I PHAR 431

Lecture Information

• Instructor: Vinayak Sant, Ph.D.

• Email: vsant@uic.edu

• Date: 27 Aug 2025

Learning Objectives

• Understand the need for dosage form design.

• Know the importance of preformulation considerations for dosage form design.

• Understand various physical and chemical properties affecting drug molecule performance.

• Grasp how these properties impact dosage form design.

Drug Development Process

Objective

• Aim to demonstrate the following for drugs:

  • Safety

  • Efficacy for intended use

  • Types of Drugs:

  • Prescription Drugs

  • Over-the-Counter (OTC) Medications

  • Generic Products

  • Biologic Products

  • Medical Devices

Definition of a New Drug

• New Drug:

  • A drug that has never been marketed in the U.S.

  • New Chemical Entity (NCE):

  • An existing drug with:

  • New dosage form

  • New route of administration

  • New delivery devices

Drug Development Stages

• Stages of Development:

  1. Drug Discovery

  2. Pre-Clinical

  3. Clinical Trials (Phase I, II, III)

  4. Regulatory Review

• Time Frames:

  • Phase I: 7 years

  • Phase II: 6.5 years

  • Phase III: 1.5 years

• Data from Stages:

  • 10,000 compounds yield 1 approved drug, taking an average of 12-15 years.

  • Average cost of development is > $1 billion.

Goals of the Drug Development Process

• Primary Goals:

  • Create effective dosage forms

  • Develop drug delivery systems

• Ultimate Goals:

  • Safety

  • Efficacy

  • Reliability

Factors Affecting Dosage Form Design

• Categories of Factors:

  1. Patient Factors

  2. Drug Molecule Factors

  3. Other Factors

Patient Perspective in Dosage Form Design

• Need to consider:

  • Flavored liquids for easier administration (especially for children)

  • Preference for forms such as oral tablets, topical patches, extended-release formulations to address fears (e.g., fear of injections)

Patient-Related Needs for Dosage Form Design

• Considerations of:

  • Therapeutic needs

  • Patient status (e.g., unconscious)

  • Nature of illness

  • Patient age groups (pediatric vs geriatric)

  • Ease of identification to minimize medication errors (size, shape, color)

Drug Molecule Considerations in Dosage Form Design

• Examples of Potent Drugs and Doses:

  • Morphine: 10 mg

  • Hydrocodone: 5 mg

  • Risperidone: 2 mg

  • Nitroglycerin: 0.4 mg

  • Misoprostol: 0.1 mg

• Characteristics Affecting Formulation:

  • Masking of taste (bitter, salty)

  • Need for optimal action from topical preparations (ointments, creams)

  • Factors requiring protection from:

  • Humidity and oxygen (e.g., coated tablets, sealed ampoules)

  • Gastric acids

  • Controlled drug action and alternate routes of administration (injection, nasal, vaginal/rectal inserts)

Drug Product and Drug Delivery System Design

Importance of Understanding:

• Thorough understanding of:

  • The drug itself

  • Disease state

  • The target site for the drug

Preformulation Studies

Importance of Preformulation

• Provides guidance in:

  • Choice of dosage form, excipients, and composition

  • Adjustments of pharmacokinetic properties:

  • Absorption (A)

  • Distribution (D)

  • Metabolism (M)

  • Elimination (E)

• Supports the development process of drug substances and products:

  • Yield, filtration, etc.

  • Provides data for analytical method development

Properties Examined in Preformulation Studies

• Physical Properties:

  • Physical form: solid, liquid, gas

  • Solubility

  • Partition coefficient

  • Particle size: distribution, flow, bulk density

  • Crystalline vs. amorphous forms

  • Polymorphism and its implications

  • Dissolution rate

  • Melting point

  • Heat of vaporization

• Chemical Properties:

  • Structure and chemical form

  • Stability (against pH, moisture, etc.)

  • Degradation profiles

  • Reactivity

  • Purity and hygroscopicity

Detailed Analysis of Physical Properties

Physical Form

• Classes:

  • Solids, liquids, gases

• Examples:

  • Gaseous forms (e.g., NO) for rapid action delivery

  • Liquid forms can be easy to administer but may have formulation issues (e.g., nitroglycerin)

  • Solid forms generally have fewer stability issues, alternatives may include soft gelatin capsules.

Solubility

• Requirement for Absorption:

  • Important for systemic absorption

  • Aqueous solubility is often pH dependent

• Strategies for Enhancing Solubility:

  • Salt or ester formation

  • pH adjustment

  • Use of cosolvents

  • Complexation techniques

• Metabolism Goals:

  • Strengthening polarity for improved excretion, including phases of metabolism (Phase I: functional group exposure; Phase II: polar group addition via glucuronide formation)

Solubility and Ionization

• Key Points:

  • Ionized forms are generally more water-soluble, whereas unionized forms are lipid-soluble.

• Clinical Relevance:

  • Ionization effects absorption in different parts of the gastrointestinal tract based on pH.

• Example Drugs:

  • Aspirin (pKa ~ 3.5): shows differences in absorption between ionized and unionized states across varying pH levels.

  • Morphine (pKa ~ 8): Similar observation in absorption behavior based on ionization.

Case Study: Drug Solubility and Dosage Forms

• **Examples:

  • Metformin (Glucophage): 1000 mg, water solubility ~ 300 mg/ml (pH 1.2-6.8), available as tablets

  • Amlodipine (Norvasc): 10 mg, water solubility ~ 0.07 mg/ml, available as tablets

  • Atorvastatin (Lipitor): 80 mg, water solubility < 1 mg/ml, available as tablets

  • Azithromycin (Zithromax): 600 mg, water solubility ~ 0.002 mg/ml, available as tablets and suspension

Particle Size

• Influence on Drug Properties:

  • Affects dissolution rates, sedimentation rates, texture, taste, stability, flow, drug content uniformity, and bioavailability.

• Examples:

  • Smaller particle sizes can enhance dissolution rates (e.g., risperidone)

• Optical Activity:

  • Different isomers can lead to varying receptor binding, as seen with propranolol where only the l-isomer is active.

Polymorphism

• Definition:

  • The existence of different crystalline forms of the same compound.

• Implications:

  • Amorphous forms usually show greater solubility compared to crystalline forms.

• Examples:

  • Compounds like chloramphenicol palmitate have several polymorphs that can affect drug behavior significantly.

Example - Ritonavir (Norvir®)

• Background:

  • An HIV protease inhibitor launched in 1996, characterized by insolubility in water. Initially marketed in capsule form.

• Development Issues:

  • Initially stable polymorph forms observed, but later batches failed dissolution tests due to transitioning to a more stable form (Form II).

  • Form II is complex to crystallize and less soluble than the original Form I.

Dissolution Rate

• Definition:

  • Rate at which drug dissolves in a medium, impacting onset, intensity, and duration of drug response and bioavailability.

Partition Coefficient (Log P)

• Biological Relevance:

  • Illustrates preference of the drug for lipid versus aqueous environments, essential to crossing biological membranes.

Chemical Properties - Degradation

Factors Affecting Degradation

• Chemical groups influence reactivity and susceptibilities.

• Common degradation paths include hydrolysis and oxidation, necessitating protective measures such as antioxidants.

Stability Provisions

• Stability refers to how well drug/drug products maintain integrity within designated limits throughout their shelf-life and under specific conditions, monitored under cGMP due to FDA guidelines.

Summary and References

• Reference Text:
  Chapter 4, Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems, Loyd V. Allen, Jr. (11th Ed), Lippincott Williams and Wilkins (2018).