Comprehensive Study Guide on Physical Pharmacy and Biopharmaceutics

Introduction to Physical Pharmacy

  • Focus on drug stability and solubilization.

  • Biopharmaceutics course overview (626/715).

Course Outline (First Half: Forrest)

  • General Topic:

    • Physical pharmacy tailored for pharmacists.

    • Key physical pharmacy concepts.

    • Overview effects on ADME (Absorption, Distribution, Metabolism, Excretion).

  • Oral Drugs:

    • Barriers to drug absorption.

    • Clearance mechanisms.

    • Strategies to enhance absorption and clearance.

    • Formulation methodologies including:

    • Infusion

    • Subcutaneous (SC)

    • Intramuscular (IM) drug formulations.

    • Methods for ensuring solubility and stability in formulations.

    • Targeting delivery of drugs.

Grading and Examination Policies

  • Exams for PharmD Students:

    • Total of 6 exams, administered via ExamSoft.

  • Graduate (PHCH/CPE715) Students:

    • Different grading system explained in a special lecture.

  • Exam Points:

    • Point values may vary (e.g., 70 or 100 points).

    • Normalization to 100 on Canvas; counts equally toward final grade.

    • Exam content focuses on material learned since the last exam but may include earlier material.

  • Last Exam:

    • Non-comprehensive, scheduled during finals.

  • Quizzes:

    • Possible pop quizzes; occurrence inversely related to attendance.

    • Pop quizzes are bonus points.

Primary Formulation Challenges

  • Objective of Drug Formulation:

    • Ensuring that drugs reach their intended site of action effectively.

    • Critical Factors:

    • Right place.

    • Right time.

    • Right concentration.

    • Correct duration of action.

    • Issues like side effects and reduced efficacy stem from violating these factors.

  • Intrinsic Challenges:

    • Drugs generally must traverse multiple biological barriers to obtain efficacy (e.g., antibiotics needing to cross the intestine, liver, and reach target sites).

    • Specific barriers:

    • Intestinal wall permeability.

    • Cell membrane passage.

    • Polar, water-soluble molecules struggle to pass biological barriers, while greasy compounds are challenged post-ingestion.

Major Problems in Drug Formulation

  • Essential Issues:

    • Solubility/dissolution of drugs.

    • Stability of drugs in their formulation.

    • Permeability and absorption factors inherent in pharmacokinetics.

    • Stability and metabolism of drugs in the body.

    • Pharmacokinetics associated with distribution and elimination.

Formulator Strategies

  • Formulation Modifications:

    • Decrease absorption rate (e.g., delayed-release formulations).

    • Increase absorption rate (e.g., sublingual, rapid dissolving, intravenous).

    • Enhance stability within formulation (e.g., utilizing prodrugs, crystal modifications).

    • Alter the site of absorption (e.g., targeting via topical, pulmonary, or ocular delivery).

    • Modify the site of pharmacological action (e.g., antibody-targeted drugs).

    • Improve metabolic stability (e.g., through the use of prodrugs or nanosized particles).

    • Manage elimination rates (not much can be done once drug is in a free state in plasma).

    • Addressing off-site effects by consideration of absorption and plasma levels, including prodrug approaches and drug targeting.

Challenges of Solubility and Stability

  • Techniques for Improving Solubility/Stability:

    • pH adjustment methods.

    • Compounding with salts.

    • Introducing co-solvents.

    • Utilizing crystalline vs. amorphous forms.

    • Employing particles and colloid formulations.

    • Designing prodrugs to enhance delivery.

Example of Drug Solubility and Required Dosing

  • Specific Case Example:

    • Water solubility: approximately 0.2 mcg/mL.

    • Daily required dose: 4 mg/kg/day for a 75 kg patient results in the need for roughly 1500 liters of IV solution.

Importance of pH and Ionization

  • Understanding Ionization:

    • Ionized, water-soluble drugs dissolve faster compared to unionized forms, which are typically lipophilic and absorb better.

    • Brønsted-Lowry Acid-Base Theory:

    • All acid-base reactions involve proton transfer.

    • Definition:

      • An acid is a proton donor.

      • A base is a proton acceptor.

    • Water can act as both.

    • Significance of dissociation in acid-base chemistry: weak acids/bases have corresponding conjugate counterparts. The strength of dissociation varies (with strong dissociating completely and weak partially).

Practical Implications of Acid-Base Chemistry

  • Relevant Acids and Bases in Pharmacy:

    • Commonly utilized acids/bases in pharmaceuticals include:

    • Strong: NaOH, HCl.

    • Weak: Salts like sodium phosphates, citrates, and diterpenoids like salicylic acid, warfarin.

    • Saline solutions and buffering agents are also crucial for stability.

Ionization and Solubility Profiles of Drugs

  • Examples:

    • Weak bases:

    • Acebutolol (pKa 9.4).

    • Affects of pH on solubility:

    • Clarithromycin (pKa 8.76), Erythromycin (pKa 8.36).

    • Practical Example of pH Influence:

    • A low pKa (<7) indicates weak acid, a high pKa (>7) often correlates to weak bases.

Drug pKa Overview

  • Key Drug pKa Values:

    • Amoxicillin (weak acid) pKa 2.4.

    • Alprenolol (weak base) pKa 9.6.

    • Other notable pKa values include:

    • Acetazolamide (7.2), Aspirin (3.5), Chlorpheniramine (9.2).

Structural Effects on pKa Variation

  • Factors Affecting pKa:

    • Local structural environments around ionizable groups.

    • Electron-withdrawing/donating groups can strengthen/weaken acid-base properties.

    • Specific examples include:

    • Trifluoroacetic acid (strong acid, pKa 0.23) vs. Acetic acid (weaker, pKa 4.76).

Pharmacological Significance of Ionization

  • Example Calculations:

    • Example with Aspirin (pKa 3.5), calculating percent ionization at specific physiological pH levels (e.g., plasma at pH 7.4).

    • Henderson-Hasselbalch Equation:

    • Formulae:

      • Overall equation: pH=pKa+extlog(rac[A−][HA])pH = pKa + ext{log}\bigg( rac{[A^-]}{[HA]}\bigg)

      • Ionized drug concentration can be derived accordingly.

Use of Buffers in Drug Formulation

  • Purpose of Buffers:

    • Stabilization of pH in drug formulations to maintain efficacy and reduce adverse reactions.

    • Common buffers (e.g., acetates, phosphates) and their pKa values corresponding to effective medicinal ranges.

Stability and Drug Forms in Development

  • Discussion on drug forms:

    • Amorphous vs. crystalline, solubility/product stability during hygroscopic storage, chemical interactions affecting solubility.

    • Descriptive analyses of hydrates, solvates, and polymorphs' properties and implications in formulation development.

Conclusion – Salting and Formulation Considerations

  • Emphasize careful selection of drug forms and salts for optimized pharmacological action, considering drug-salt interactions, pharmacokinetics, and patient-centric considerations regarding formulation and stability.

Additional Topics

  • Introduction to cyclodextrins as complexing agents impacting drug solubility and handling various environmental stresses in formulation.

  • Exploring economic aspects of traditional vs modular drug development strategies, especially focusing on salting and modifying molecular properties effectively.

Appendix: Tables and Graphs Showing pKa Values, Solubility Profiles, and Examples of Drug Salting Effects

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Comprehensive Notes: Drug Formulation and Physical Pharmacy

Main Takeaway

Drug formulation is critical for ensuring medications reach the right place, at the right time, in the right concentration, and for the correct duration while remaining stable. This often involves overcoming inherent physicochemical challenges of drug molecules, primarily solubility, permeability, and stability, through various formulation strategies.

1. Introduction to Drug Formulation

• Purpose: To enable effective administration of medications to patients.

• Practical Focus: This course emphasizes real-world applications of drug formulation and the practical aspects of various dosage forms.

• Instructor's Background: PhD in gene therapy (quarter century ago), noted the shift from abstract research to real-world application (e.g., COVID vaccine as a form of gene therapy).

2. Course Outline (First Half - Forrest)

• General Topics:

• Physical Pharmacy: Important concepts, overview of effects on ADME (Absorption, Distribution, Metabolism, Excretion).

• Oral Drugs: Barriers, clearance, approaches to improve absorption/clearance, formulation methods.

• Infusion/Subcutaneous (SC)/Intramuscular (IM) Drug Formulation: Solubility/stability methods, targeting.

• Guest Speakers (Dr. Howell and Dr. Kim): Cover topical, ocular, nasal delivery, protein therapeutics, gene therapy, and complex biologics.

3. Grading

• PharmD/Undergraduate Students:

• 6 Exams: Non-comprehensive, given via ExamSoft, normalized to 100 points on Canvas, count equally. Last exam on finals day.

• Quizzes: Possible pop quizzes, bonus points, inversely correlated with attendance.

• Graduate Students (PHCH/CPE715): Online quizzes, grade mostly based on reports from Dr. Howell's AI lectures.

4. The Challenges of Drug Formulation

• Goal Violation: Side effects and poor efficacy typically arise when the drug fails to reach the target site at the right time/concentration/duration, or lacks stability.

• Inherent Drug Properties: Drug molecules are often highly specific with defined interactions, leaving little room for modification of their fundamental physical properties.

• Body Barriers: Most drugs must pass through various biological barriers (e.g., GI wall, cell membranes) to reach their site of action.

• Example: Topical drugs directly applied, but still must cross epidermis. Beta-blockers must travel extensively.

• Physicochemical Dilemma:

• Body is mostly water (needs water-soluble drug for dissolution/transport).

• Contains many lipid membranes (needs lipophilic/greasy drug for permeability).

• Requires a balance of both properties.

• Biggest Problems for Formulators:

1. Solubility / Dissolution: Getting the drug into solution.

2. Drug Stability: In the formulation and within the body.

3. Permeability / Absorption (Pharmacokinetics): Getting drug across membranes.

4. Elimination / Distribution (Pharmacokinetics): Maintaining therapeutic levels.

5. What Formulators Can Do (Strategies from Easiest to Hardest)

• Sustain Release: Alter absorption rate (e.g., immediate vs. 24-hour Sudafed).

• Increase Stability in Formulation: (e.g., tablet form for water-unstable drugs).

• Change Site of Pharmacological Action: (e.g., antibody-drug conjugates for targeted chemotherapy).

• Improve Stability to Metabolism: (e.g., prodrugs, IV administration to bypass first-pass metabolism).

• Address Rapid Elimination Rate: (Very difficult, sometimes impossible; e.g., 20g/day subcutaneous protein drug example).

• Off-Site Targeting Problems: (Extremely tough to fix).

6. First Challenge: Solubility and Stability

6.1. Methods for Solubility and Stability

• pH Adjustment

• Salts

• Co-solvents

• Crystals / Amorphous Systems

• Particles and Colloids

• Prodrugs

6.2. The Big Picture: Ionization & pH

• Dissolution: Ionized and water-soluble drugs tend to dissolve faster (due to strong dipole interactions with water).

• Absorption: Unionized and lipid-soluble drugs tend to absorb better across biological membranes.

• Challenge: Many drugs must be reversibly ionizable to dissolve in aqueous environments (e.g.

Jeifannie, [2/6/2026 3:57 PM]

, GI fluid, blood) and then become unionized to cross lipid membranes.

• Example: Amphotericin B: Extremely low solubility (~0.2 µg/mL). Without formulation tricks, a single dose would require ~1,500 L of fluid for IV administration.

6.3. Acid-Base Theories

• Brønsted-Lowry Theory:

• Involves the transfer of a proton (H+).

• Acid: Proton donor. Base: Proton acceptor. Water can act as both.

• Weak acids/bases partially dissociate in water, maintaining equilibrium.

• Strong acids/bases dissociate completely (e.g., HCl, NaOH).

• Clinical Relevance: A vast majority of drugs (~50%) are weak acids or bases, often formulated as salts to enhance solubility.

• Example: Sertraline HCl (Zoloft®): Free base is permeable but insoluble. Reaction with HCl gas creates a polar, soluble salt that precipitates out for tablet formation.

• Lewis Acid-Base Theory:

• Involves the transfer of electrons.

• Acid: Accepts electrons. Base: Donates electrons.

• Less common for typical drug ionization but relevant for some molecules (e.g., Cisplatin).

6.4. Ionization and Solubility Examples

• Weak Base (Acebutolol, Clarithromycin, Erythromycin):

• Solubility increases significantly as pH becomes more acidic (drug becomes more ionized).

• Acebutolol: 0.5 µg/mL (alkaline) to 200 mg/mL (neutral).

• Clarithromycin/Erythromycin: Insoluble at pH 10, ~3-4 mg/mL at pH 7.

• Weak Acid (Naproxen, Aspirin):

• Solubility increases significantly as pH becomes more alkaline (drug loses proton, becomes more ionized).

• Naproxen: 16 µg/mL (low pH) to 260 mg/mL (pH ~7.5), a ~10,000-fold increase.

• Zwitterion (Amoxicillin):

• Low solubility (<1 mg/mL) at neutral pH because opposing charges cancel out.

• Higher solubility (>10 mg/mL) at highly acidic or alkaline pH where only one ionizable group is predominantly charged.

6.5. Determining Acid/Base Nature and pKa

• pKa: The pH at which 50% of the drug molecule is ionized and 50% is unionized.

• Note: pKa value alone does not indicate whether a molecule is an acid or a base.

• Structure is Key: Recognizing functional groups (e.g., carboxylic acid, amine) is crucial.

• Aspirin (Weak Acid, pKa 3.5): Carboxylic acid group.

• Low pH (high H+): Equilibrium shifts to unionized form, insoluble.

• High pH (low H+): Equilibrium shifts to ionized form, soluble.

• Factors Affecting pKa: Local electron environment, electron-withdrawing groups (e.g., fluorines in trifluoroacetic acid, pKa 0.23, making it a stronger acid than acetic acid, pKa 4.76).

• Henderson-Hasselbalch Equation: Can be used to calculate the percentage of ionized/unionized species at a given pH.

6.6. Impact of Ionization on Pharmacology and Pharmacokinetics

• Aspirin (pKa 3.5): In plasma (pH 7.4), ~99.99% is ionized.

• Active Form: The 0.01% unionized portion is actually active, as it can diffuse through the hydrophobic channel to the COX enzyme. The ionized form serves as a large pool.

• Renal Clearance (Kidney Function): Primary route of drug elimination.

• Glomerular Filtration: Size-selective sieve. Molecules < 70,000 Da are filtered; < 10,000 Da are completely sieved. Plasma proteins (e.g., albumin, ~70,000 Da) are not filtered.

• Proximal Tubule: Actively secretes water-soluble drugs, creatinine, uric acid into the filtrate.

• Loop of Henle: Reabsorbs water, concentrating the filtrate (from ~300 mOs to ~1,400-2,000 mOs). This increases drug concentration.

• Distal Tubule: Lipid-permeable.

• If drug is unionized and lipid-soluble, its high concentration in the tubule drives passive reabsorption back into the blood.

• Urine pH Influence:

• Weak Acid (e.g., Indobufen, furosemide):

• Acidic urine: Drug becomes more unionized, leading to increased reabsorption and longer plasma half-life.

• Alkaline urine: Drug becomes more ionized, leading to decreased reabsorption and faster elimination.

• Weak Base (e.g., Methamphetamine, Amphetamine, Mexiletine):

• Alkaline urine: Drug becomes more unionized, leading to increased reabsorption and longer plasma half-life.

• Acidic urine: Drug becomes more ionized, leading to decreased reabsorption and faster elimination.

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• Example: Amphetamine study showed patients with acidic urine had short-lived effects, while those with alkaline urine experienced prolonged effects.

6.7. Common Ionizable Structures (Acids)

• Carboxylic Acids: (e.g., Naproxen, Aspirin) pKa usually < 5. Soluble in alkaline conditions.

• Phenols: (e.g., Tylenol, Estrogen, Propofol, Diethylstilbestrol (DES)) pKa ~9-11. Stronger acids than alcohols due to resonance stabilization. Can ionize at physiological pH.

• Example: Propylparaben (preservative) added in alkaline solution for solubility.

• Enols/Enolates (Resonance-stabilized): (e.g., Warfarin, Phenprocoumon)

• Warfarin (pKa 5.06): Weaker acid than phenprocoumon (pKa 3.77) due to its ability to form a hemiacetal, stabilizing the unionized form.

• Warfarin Protein Binding: Highly bound to serum albumin (a major carrier of lipophilic molecules).

• Non-Esterified Fatty Acids (NEFA) Effect: NEFAs compete for albumin binding sites.

• Moderate NEFA: May increase warfarin-albumin binding, reducing free drug and efficacy.

• High NEFA: May displace warfarin from albumin, increasing free drug and biological action. This complexity contributes to difficulties in warfarin management.

• Amides (with acidic carbons/nitrogens):

• Phenylbutazone (pKa 4.4): A weak acid, not a base, despite having nitrogens. The acidic proton is on a carbon between two ketones, stabilized by resonance.

• Phenobarbital (pKa 7.44): Nitrogens act as acids due to electron-withdrawing oxygens. Alkalanizing blood (e.g., IV sodium carbonate) increases ionization and elimination, useful in phenobarbital poisoning.

• Barbiturates: All are weak acids, cyclic imide structures. Their plasma half-lives are directly correlated with pKa (low pKa -> shorter half-life; high pKa -> longer half-life).

• Sulfonamides: Nitrogens act as acids (pKa 5-10) due to neighboring electronegative atoms.

6.8. Common Ionizable Structures (Bases)

• Amines: (e.g., Terfenadine, Procaine, Methamphetamine) Nitrogen with a lone pair accepts a proton.

• More soluble in acidic conditions (more H+).

• *Terfenadine (