Acids and Bases. Moore, T. (2016). Acids and Bases. Lecture presented at PHAR 422 Lecture in UIC College of Pharmacy, Chicago.

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1 Acids and Bases Moore, T. (2016). Acids and Bases. Lecture presented at PHAR 422 Lecture in UIC College of Pharmacy, Chicago. Drug dissolution can impact buffering capacity of the body Most enzymes require drug to be charged to bind Drug must be neutral to pass through cell membranes / blood brain barrier (BBB) Charged drug = specific binding = more soluble Ex) Memantine clearance = organic base. When urine more basic, the molecule becomes charged and can t be reabsorbed. Drug build up in body, can become toxic pka = measure of acidity o Topical drugs have amount of drug that exceeds the physiologic buffer the pka and state of the drug can impact the buffer ph o Ionization state usually determined by pka of the drug in buffer when the drug does not exceed the buffer capacity o Ionization state of the drug determines its absorption, solubility, and binding to albumin Bronsted acid any molecule that can donate a proton Bronsted base any molecule that can accept a proton A Bronsted acid will have a conjugate base and vice versa ** Another way of thinking of an acid and base is that an acid accepts a pair of electrons while a base donates a pair of electrons. This might make it easier to predict why certain electron withdrawing/donating groups make things more or less acidic/basic.

2 A base in solution will increase the ph of the solution An acid in solution will decrease the ph of the solution Amphoteric molecules can act as acids and bases = buffers o main example is bicarbonate in the blood Strong acid means it dissociates in water easily o Relative strength based on ability to donate a proton o Equilibrium favors the weaker acid Ka is a quantitative way of measuring the strength of an acid o Higher Ka, more acidic o pka = -log(ka) *** Remember that knowing how a drug will dissociate in solution is all dependent on RELATIVE acidity and basicity. The majority of the time the solution is going to be water, with a pka around 16. If the molecule is more acidic (lower pka), it will act as an acid. If the molecule is more basic (higher pka), it will act as a base.

3 Strong Acids HCl (hydrochloric acid) HNO 3 (nitric acid) H 2 SO 4 (sulfuric acid) HBr (hydrobromic acid) HI (hydroiodic acid) HClO 4 (perchloric acid) HClO 3 (chloric acid) Weak Acids H 3 PO 4 (phosphoric acid) HNO 2- (nitrous acid) C 6 H 5 COOH (benzoic acid) CH 3 COOH (acetic acid) HCOOH (formic acid) H s S (hydrogen sulfide) HCN (hydrogen cyanide) Strong Bases LiOH (lithium hydroxide) NaOH (sodium hydroxide) KOH (potassium hydroxide) RbOH (rubidium hydroxide) Sr(OH) 2 (strontium hydroxide) Ba(OH) 2 (barium hydroxide) Weak Bases CO 3 2- (carbonate ion) CH 3 NH 2 (methyl amine) NH 3 (ammonia) HCO 3- (bicarbonate) C 5 H 5 N (pyridine) C 6 H 5 NH 2 (aniline) Ca(OH) 2 (calcium hydroxide) Zn(OH) 2 (zinc hydroxide)

4 STUDY TIP: Have a good idea of what are strong acids and bases. If you know these, you will automatically know if something is a weak acid or base. This will make it easier to predict equilibrium Strong base + strong acid in water give neutral solution Weak acid + strong base in water give slightly basic solution (ph>7) b/c increases hydroxyl ion concentration (-OH) Strong acid + weak base in water gives slightly acidic solution (ph<7) b/c increases hydronium ion concentration (H3O + ) Salts of a strong acid + a weak base gives an acidic solution o Examples of salts of strong acids: ZnCl2, Ca(NO3)2, Zn(ClO4)2, CaSO4, Ca3(PO4)2 Salts of a strong base + a weak acid gives a basic solution o Examples of salts of strong bases: Na2CO3, KCN, Na2S K eq gives concentrations of components at equilibrium A + B C + D Keq = [C][D] [A][B] K a acid dissociation constant HX + H2O X - + H3O + Ka = Keq * [H2O] = [X - ][ H3O + ] [HX] Larger Ka means stronger acid pka = -log(ka) pka < 2 = strong acid pka 4-6 = weak acid pka 8-10 = weak conjugate base pka >12 = strong conjugate base Equilibrium favors the side of the weaker acid and weaker base

5 Henderson-Hasselbalch Equation gives idea of how many groups are ionized ph = pka + log [conjugate base] acid ph = -log[h + ] Water participates in acid/base equilibrium o Strong acids dissociate completely, so the hydronium ion then becomes the strongest acid in solution = leveling effect o Strong bases dissociate completely, so the hydroxide ion then becomes the strongest base in solution Basic amine groups are used to neutralize a drug to allow it to pass through BBB REMEMBER: Ionized just means CHARGED. Doesn t necessarily mean proton vs. no proton. For example, with H 2O and H 3O + the ionized form is the positively charged hydronium

6 Buffers Buffer = a solution that resists changes in ph even when acids and bases are added o Titration curve will look flat where ph = pka o Ex) Tris, MES, HEPES, MOPS, PIPES Alcohol functional groups are found in 20% of drugs o Have pka around 16 o Are more acidic when near electronegative groups b/c the negative charge it gets when it loses the proton (when it becomes an alkoxide) can be stabilized by induction The reason branched alcohols are less acidic is because there is steric hinderance that blocks the negative charge (if it loses a proton) from being stabilized by hydrogen bonding with water Normally, alcohols, thiols, and ethers are considered weak Bronsted Lowery bases and exist undissociated in water Phenols o When electron withdrawing group is on the ring, it increases the acidity because they help to stabilize the negative charge when the proton is lost Ex) Nitrate group para to the hydroxyl o When electron donating group is on the ring, it decreases the acidity Ex.) CH3 group on the ring

7 Amines o Has unshared pair of electrons so acts as a base o The order of basicity is usually secondary > tertiary > primary. Tertiary is more than primary because the methyl groups act as electron donors and stabilize the added proton. The secondary is more than tertiary because there is less steric hinderance to accept the proton o When attached to an aromatic ring, the aromatic ring draws electrons in and decreases the basicity of the amine group b/c it s harder for the amine to give up the electrons now Carboxylic acids o Similar to phenols. When attached to electron withdrawing group, acidity increases. When attached to electron donating group, acidity decreases.

8 pka of Amino Acids MEMORIZE Asp/Glu pka: Ser/Thr pka: Cys pka: His pka: Arg pka: Tyr pka: Lys pka: Amino acids act as natural buffers Many drugs formulated as salts to help with absorption and delivery Solubility is ph dependent o At some point, salt stops dissolving = equilibrium solubility Partition Coefficient: LogP P = [drug]octanol [drug]water Higher logp means the drug is more lipophilic ph must be at a value where the drug is unionized to use this equation

9 Distribution Coefficient: LogD P = [drug]ionized octanol + [drug]unionized octanol [drug]ionized aq + [drug]unionized aq LogD takes into account ionization state of the drug With higher ph, the drug becomes ionized and moves out of the octanol phase into the aqueous phase The higher ph, the lower logd value. Lower logd value means more hydrophilic drug