5. 21 Acids, Bases and Salts

Nitrogen Basics and Functional Groups

  • Basic Nitrogen: A is the correct answer; it's a basic nitrogen.
  • Functional Groups: Make cards to learn the functional groups; drawing dissociation equations is important for acid-base questions.
  • Incorrect Options: B is incorrect because a negative charge wouldn't be stabilized. C is also incorrect.

Phenolic Hydroxyl Group

  • Correct Dissociation: The correct association is B, a phenolic hydroxyl group, which is an acidic functional group that can donate and stabilize a negative charge.

Amides

  • Amide Neutrality: Amides are neutral; they don't pick up or donate protons. This is a tricky point.
  • Charge Balance: In dissociation equations, the charge must balance on both sides of the equation.
  • Basic Amine: B is correct; it's a basic aliphatic amine that picks up a proton.

pKa and Structure

  • pKa Consideration: You can't determine acidity or basicity just by the pKa; look at the structure.
  • Drug Classification: Classify drugs based on functional groups; drugs have multiple ionizable functional groups.
  • Acidic Drugs: Contain one or more acidic functional groups but no basic groups.
  • Basic Drugs: Contain one or more basic functional groups but no acidic groups.

Amphoteric Drugs

  • Amphoteric Drugs: Contain at least one acidic and one basic functional group (like amino acids).
  • Zwitterions: Drugs are often insoluble at their zwitterion point, where positive and negative charges cancel out at a specific pH.

Neutral Drugs

  • Neutral Drugs: Contain zero ionizable functional groups.

Practice Classification

  • Classification Exercise: Classify compounds on the left as acidic, basic, amphoteric, or neutral.
  • Basic Functional Groups: The first compound has two basic functional groups.
  • Amid Group: The presence of an amid group makes the compound neutral.
  • Acidic Protons: Two carboxylic acids indicate acidic protons.

Identifying Amphoteric Compounds

  • Amphoteric Identification: The compound is amphoteric due to having both basic and acidic functional groups.

Weaker Bases

  • Most Basic Nitrogen: In the next compound, the circled nitrogen is the most basic.
  • Weakly Basic Nitrogen: The dashed nitrogen is weakly basic due to sterics and electron withdrawal into the aromatic ring.
  • Neutral Nitrogen: One nitrogen is essentially neutral as its electrons are fully involved in the aromatic ring.

Acidic Functional Groups

  • Acidic Groups: The third drug has a basic aniline nitrogen, a carboxylic acid, and a phenolic hydroxyl (acidic because it's on an aromatic ring, making it a phenol).

Importance of Acid-Base Chemistry

  • Drug Ionization: It's important to know if a drug is ionized at specific pHs.
  • Water Solubility: Ionized drugs (with positive or negative charges) are more water-soluble, aiding dissolution.

Water Solubility and Drug Administration

  • IV Solutions: Necessary for IV solutions, ophthalmic, and otic solutions.
  • Drug Elimination: Ionized drugs are more readily eliminated via urine as they don't get reabsorbed easily.
  • Toxicity Management: Adjusting urine pH can help excrete drugs during toxicity or overdose.

Unionized Drugs

  • Cell Membrane Permeability: Unionized drugs cross cell membranes more easily (GI tract, drug target).
  • Blood-Brain Barrier: Unionized drugs cross the blood-brain barrier, which can be good or bad depending on the drug's purpose and side effects.
  • Fat Trapping: Unionized drugs can be trapped in fat, leading to longer durations of action, especially in obese patients.

Plasma Protein Binding

  • Drug Activity: Drugs are only active when free (not bound to plasma proteins).
  • Acidic Drug Binding: Acidic drugs bind to albumin.
  • Basic Drug Binding: Basic drugs bind to alpha-1 acid glycoprotein.

Learning Objectives

  • Revisiting Concepts: Review and expand on solubility and salt formation.
  • Chapter Focus: Salts are now in Chapter 5, while previous topics were in Chapter 3.

Types of Pharmaceutical Salts

  • Salt Types: Three main types of salts: water-soluble inorganic, water-soluble organic, and lipid-soluble organic.

Salt Formation Requirements

  • Charge Requirement: Salts need a charge; the drug molecule must have a functional group that can be drawn in a dissociation equation.
  • Neutral Drug Inability: Neutral drugs can't form salts due to the lack of positive or negative charges.

Water-Soluble Inorganic Salts

  • Inorganic Composition: Water-soluble inorganic salts don't contain carbon; examples include potassium hydroxide, calcium hydroxide, and sodium hydroxide (bases reacting with acidic drugs).
  • Acidic Salt Examples: Hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid (reacting with basic drugs).
  • Salt Formation Principle: An acidic functional group reacts with a base to form a salt, and vice versa.

Importance of Understanding Salts

  • Salt Neglect in Pharmacy: Salts are often ignored in pharmacy school.
  • Prevalence of Salts: Over 50% of drugs on the market contain a salt, making their understanding crucial.

Inorganic Salts: Potassium Salts

  • Ionic Compound Formation: Salts are ionic compounds formed when an acid reacts with a base.

Penicillin as an Acid

  • Penicillin Classification: Penicillin is an acidic drug.
  • Neutral Amid Groups: Recognize amid groups; they are neutral and do not form dissociation equations.
  • Dissociation Reaction: Penicillin loses a proton and becomes negatively charged (O−O^-, D stands for dissociation).
  • Base Reaction: Acids react with bases, in this case, potassium hydroxide.
  • Salt Formation: The reaction forms a salt, with potassium as the counterion.
  • Salt Name: The resulting salt is called penicillin potassium.

Salt Solubility and Bond Strength

  • Covalent vs. Ionic Bonds: Covalent bonds (O-H in penicillin) are strong and require energy to break.
  • Ionic Bond Weakness: Ionic bonds (between oxygen and potassium in the salt) are weaker and dissociate easily.
  • Water Molecule Interaction: Water molecules can easily dissolve ionic bonds, making the salt water-soluble.
  • Solution Preparation: Salt forms help make solutions, important for oral and IV administration.

Alternative Salt Forms and Patient Considerations

  • Sodium Hydroxide Reaction: Penicillin can react with sodium hydroxide to form penicillin-sodium.
  • Hospital Availability: Both penicillin-potassium and penicillin-sodium are available in hospitals.
  • Electrolyte Load: High doses of penicillin can lead to significant sodium or potassium intake, important for patients with specific therapeutic statuses.

Assessing Drug Properties and Salt Formation

  • Amphoteric Drug Identification: Determine if a drug is acidic, basic, amphoteric, or neutral.
  • Manufacturer Choice: With amphoteric drugs, manufacturers can choose to react them with an acid or a base to form a salt.

Theuridazine: A Basic Drug

  • Basic Functional Group Identification: Identify the acidic or basic functional group in the drug structure.
  • Theuridazine Classification: Theuridazine is a basic drug with no acidic functional groups.
  • Most Basic Nitrogen: The bottom nitrogen is more basic than the top nitrogen between the aromatic rings.
  • Neutrality of Top Nitrogen: The electrons of the top nitrogen are highly delocalized, making it effectively neutral.
  • Salt Formation: The basic nitrogen reacts with hydrochloric acid to form the salt.
  • Counterion: Chloride is the counterion in this case.
  • Importance of Dissociation Equations: Being able to draw dissociation equations are crucial for forming salts on drugs, because salts are always formed with the ionized form of the drug.

Multiple Benefits of Salt Formation

  • Shelf Stability: Salts can increase the shelf stability of a drug.
  • Ease of Formulation: Improved flow and handling during manufacturing.
  • Absorption Improvement: Enhanced dissolution leads to better absorption of the drug.
  • Duration of Action: Salt forms can modify the duration of action, primarily with lipophilic salts.

Therapeutic Concerns and Salt Selection

  • Salt Therapeutic Concerns: Primary therapeutic concern is the amount of sodium or potassium administered.
  • Electrolyte Restriction: Important consideration for cardiac or NICU patients with sodium or potassium restrictions.
  • Salt Selection: The correct salt form is formed based on knowing the dissociation and functionality of the structures present.

Water-Soluble Organic Salts (Carbon-Containing)

  • FDA Approval: The FDA must approve the salt form to ensure it is non-toxic.
  • Organic Acid Examples: Basic drugs can react with citric acid or malic acid.
  • Basic Counterion Examples: Acidic drugs can react with tromethamine and ethanolamine.
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