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Chapter: Pharmaceutical Drugs and Dosage: Pharmaceutical considerations

Pharmaceutical Drugs and Dosage: Pharmaceutical considerations - Review questions and answers


Review questions

3.1 Which of the following statements is FALSE?

A.      The partition coefficient is the ratio of drug solubility in n-octanol to that in water.

B.      Absorption of a weak electrolyte drug does not depend on the extent to which the drug exists in its unionized form at the absorp-tion site.

C.      Amorphous forms of drug have faster dissolution rates than crys-talline forms.

D.      All of the above.

3.2 The pH of a buffer system can be calculated with:

A.      Henderson–Hasselbalch equation

B.      Noyes–Whitney equation

C.      Michaelis–Menten equation

D.      Yang’s equation

E.       All of the above

3.3 Indicate which of the following statement are TRUE and which are FALSE:

A.      Henderson–Hasselbalch equation describes the effect of physical parameters on the stability of pharmaceutical suspensions.

B.      The passive diffusion rate of hydrophobic drugs across biological membranes is higher than that of hydrophilic compounds.

C.      Factors influencing dosage form design do not include drug solubility and pH but include partition coefficient and pKa values.

D.      Drug solubility can be enhanced by salt formation, use of cosolvent, complex formation, and micronization.

3.4 A. What is the difference between drug adsorption and drug absorption?

B. Describe the pH-partition theory and its limitation in relation to drug absorption across the GI tract.

C. Compare any two compounds differing in the following character-istics and suggest which one would be absorbed more efficiently and why:

i. A water-insoluble compound versus a highly soluble compound.

ii. A low molecular weight compound versus a high molecular weight compound.

3.5 A. Why do we need to formulate a drug into a pharmaceutical dosage form?

B. Define partition coefficient and log P.

C. Define electrolytes and nonelectrolytes.

3.6 A. Enlist eight intrinsic characteristics of a drug substance that must be considered before the development of its pharmaceutical formulation.

B. Enlist two limitations of pH-partition theory.

3.7 Define pH-partition theory. The pKa value of aspirin, which is a weak acid, is about 3.5. What are the ratios of ionized and unionized forms of the drug in the stomach (pH 2) and in the plasma (pH 7.4)? Why does aspirin often cause gastric bleeding?

3.8 Enlist six physicochemical properties of a drug that influence absorp-tion. How can the physicochemical properties be improved to increase drug absorption?

3.9 The pKa of pilocarpine is 7.15 at 25°C. Compute the mole percentage of free base present at 25°C and a pH of 7.4.

3.10 Calculate the percentage of cocaine existing as the free base in a solu-tion of cocaine hydrochloride at pH 4.5 and pH 8.0. The pKa of cocaine is 5.6.

3.11 For a weak acid with a pKa of 6.0, calculate the ratio of acid to salt at pH 5.


Answers:

3.1 B. According to the pH-partition theory, absorption of a weak elec-trolyte drug depends on the extent to which the drug exists in its unionized form at the absorption site. However, the pH-partition theory often does not hold true, as most weakly acidic drugs are well absorbed from the small intestine because of the large epithe-lial surface areas of the organ.

3.2 A. The Henderson–Hasselbalch equation for a weak acid and its salt is represented as pH = pKa + log [salt]/[acid], where pKa is the negative log of the dissociation constant of a weak acid and [salt]/ [acid] is the ratio of the molar concentration of salt and acid used to prepare a buffer.

3.3 A. False

B. True

C. False

D. True

3.4 A. Adsorption is different from absorption, which implies pen-etration through organs and tissues. The degree of adsorption depends on the chemical nature of the adsorbent and the adsor-bate, surface area of the adsorbent, temperature, and partial pres-sure of the adsorbed gas. Adsorption can be physical or chemical in nature.

B. The pH-partition theory states that drugs are absorbed from the biological membranes by passive diffusion, depending on the fraction of unionized form of the drug at the pH of that biologi-cal membrane. Their degree of ionization depends on both their pKa and the solution pH. The GI tract acts as a lipophilic bar-rier and thus ionized drugs will have minimal membrane perme-ability compared to unionized form of the drug. The solution pH will affect the overall partition coefficient of an ionizable substance. The pKa of the molecule is the pH at which there is a 50:50 mixture of conjugate acid–base forms. The conjugate acid form will predominate at a pH lower than the pKa, and the conjugate base form will be present at a pH higher than the pKa. The following Henderson–Hasselbalch equations describe the relationship between ionized and nonionized species of a weak electrolyte:

Weakly Acidic Drugs

pH = p Ka + log[A ]/[HA]

Weakly Basic Drugs

pH = pKa + log[ B ]/[BH+]

The pH-partition theory often does not hold true. For example, most weak acids are well absorbed from the small intestine, which is contrary to the prediction of the pH-partition hypothesis. Similarly, quaternary ammonium compounds are ionized at all pHs but are readily absorbed from the GI tract. These discrep-ancies arise because the pH-partition theory does not take into account the following:

·           Large epithelial surface areas of the small intestine compensate for ionization effects.

·           Long residence time in the small intestine also compensates for the ionization effects.

·           Charged drugs, such as quaternary ammonium compounds, may interact with oppositely charged organic ions, resulting in a neutral species, which is absorbable.

·           Some drugs are absorbed via active pathways.

C. i. A highly water-soluble compound will be absorbed poorly as compared to lipophilic compounds.

ii. A low-molecular weight compound will be absorbed better than a high-molecular weight compound.

3.5 A. Besides providing the mechanism for the safe and convenient deliv-ery of accurate dosage, we need to formulate a drug into pharma-ceutical dosage forms for the following additional reasons: (i) to protect the drug substance from the destructive influence of atmo-spheric oxygen or humidity;(ii) to protect the drug substance from the destructive influence of gastric acid after oral administration; (iii) to conceal the bitter, salty, or offensive taste or odor of a drug substance; (iv) to provide liquid preparations of substances that are either insoluble or unstable in the desired vehicle; (v) to pro-vide rate-controlled drug action; and (vi) to provide site-specific drug delivery.

B. A drug’s partition coefficient is a measure of its distribution in a lipophilic–hydrophilic phase system and indicates its ability to penetrate biological membranes. The octanol–water parti-tion coefficient is used in the formulation development and is defined as P = (concentration of drug in octanol or nonpolar solvent)/(concentration of drug in water polar solvent). The log-arithm of partition coefficient (P) is known as log P. The value of log P is a measure of lipophilicity and is used widely because many pharmaceutical and biological events depend on lipophilic characteristics.

C. Nonelectrolytes are substances that do not form ions when dissolved in water. Their aqueous solutions do not conduct an electric current. Electrolytes are substances that form ions in solution. As a result, their aqueous solutions conduct electric current. Electrolytes are characterized as strong or weak. Strong electrolytes (e.g., sodium chloride and hydrochloric acid) are completely ionized in water at all concentrations. Weak electrolytes (e.g., aspirin and atropine) are partially ionized in water.

3.6 A. Eight intrinsic characteristics of a drug substance that must be considered before the development of its pharmaceutical formula-tion are the following:

Drug solubility and pH: A drug substance must possess some aqueous solubility for systemic absorption and therapeu-tic response. Enhanced aqueous solubility may be achieved by forming salts or esters, by chemical complexation, or by reducing the drug’s particle size. The pH affects solubility and stability. Cosolvents, complexation, micronization, and solid dispersion are used to improve aqueous solubility.

Partition coefficient: The partition coefficient of a drug is a measure of its distribution in a lipophilic–hydrophilic phase system and indicates its ability to penetrate biological membranes.

Dissolution rate: The speed at which a drug substance dis-solves in a medium is called its dissolution rate.

Polymorphism: Polymorphic forms exhibit different physico-chemical properties, including melting point and solubility, which can affect the dissolution rate and thus the extent of its absorption.

Stability: The chemical and physical stability of a drug sub-stance alone, and when combined with formulation compo-nents, is critical to prepare a successful pharmaceutical product. For drugs susceptible to oxidative decomposition, the addition of antioxidant stabilizing agents to the formulation may be required to protect potency. For drugs destroyed by hydroly-sis, protection against moisture in formulation, processing, and packaging may be required to prevent decomposition.

Membrane permeability: To produce a biological response, the drug molecule must first cross a biological membrane. The biological membrane acts as a lipid barrier to most drugs and permits the absorption of lipid-soluble substances by passive diffusion, whereas lipid-insoluble drugs can diffuse across the barrier only with considerable difficulty.

Partition coefficient: The octanol–water partition coefficient is used in formulation development. P = (concentration of drug in octanol)/(concentration of the drug in water).

pKa/dissociation constants: The extent of ionization or dissocia-tion is dependent on the pH or the medium containing the drug.

B.  The pH-partition theory often does not hold true, as most weakly acidic drugs are well absorbed from the small intestine, possibly because of the large epithelial surface areas of the organ. Drugs have a relatively long residence time in the small intestine, which also compensate for ionization effects.

3.7 According to the pH-partition theory, absorption of a weak elec-trolyte drug depends on the extent to which the drug exists in its unionized form at the absorption site. According to the Henderson– Hasselbalch equation

pKa = pH + log( [HA]/[A] )


log Cu/ Ci = p Ka pH

log Cu/ Ci  = 3 .5 2 = 1.5

where:

Cu is the concentration of unionized drug

Ci is the concentration of ionized drug

Cu / Ci  = antilog 1.5 = 31.62:1

In the plasma

pKa = pH + log [HA]/[A−]

log Cu/ Ci = p Ka − pH

log Cu/ Ci = 3 .5 − 7 . 4 = −3.9

Cu/ Ci = antilog ( − 3 .9) = 0.00125

Therefore, most of the administered aspirin remains unionized in the stomach and thus it is rapidly taken up by the stomach, leading to gastric bleeding.

3.8 Six physicochemical properties of a drug that influence drug absorp-tion are (1) molecular weight, (2) drug solubility, (3) pKa, (4) log P, (5) polymorphism, and (6) stability. Physicochemical properties of a drug can be improved by salt formation, bioconjugation, the use of cosolvents, and its use as a prodrug.

3.9


3.10 p Kb + pKa = p K w , p Ka = pK w p Kb,pKa = 14. 0 5.6 = 8.4

At pH 4.5,


3.11 pH = pKa + log [salt]/[acid], 5 .0 = 6 . 0 + log [salt]/[acid]

[acid] /[salt]= antilog(1.0) = 10:1

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