PHRM 898 Dosage Forms I Drug Stability Section Homework Due Date: Wednesday, October 31st, 5 pm Instructions: Answer

r each of the questions below. Show your work in the space provided and enter your final answer in the box. When units are listed beside the box, your numerical answer must correspond to these units. Prepare a PDF of your completed homework and upload to the Blackboard site before the deadline. Be sure to write your NAME on this cover sheet before uploading. Grading Rubric: For each question, points will be assigned according the following grading scheme: Correct answer, correct and complete work shown 5 pts Correct answer, incomplete or missing work 3 pts Incorrect answer, work shown 2 pts Incorrect or no answer, no work shown 0 pts

NAME____________________________________________________________________

Sources: J.K.H. Ma and B.W. Hadzija, Basic Physical Pharmacy, Jones and Bartlett Learning, LLC, Burlington, MA, 2013. ISBN 978-0-7637-5734-2 ISBN 0-7637-5734-9 M. Bi, J. Singh, Effect of buffer pH, buffer concentration and skin with or without enzyme inhibitors on the stability of [Arg8]-vasopressin. International Journal of Pharmaceutics, 197: 87-93, 2000. G.E. Granero, G.L. Amidon, Stability of valacyclovir: Implications for its oral bioavailability. International Journal of Pharmaceutics, 317:14-18, 2006.

1) The half-life of a drug that decomposes by first-order kinetics is 55 days. What is the first-order degradation rate constant?

days-1

2) The first-order rate constant for procaine degradation at 40 oC is 0.011 s-1. The activation energy is 13,800 cal/mol. Calculate the half-life at 10 oC.

hours

3) The rate constants of a reaction at 45 and 25 oC were found to be 0.045 and 0.006 min-1, respectively. Estimate the activation energy (Ea) for the reaction.

kcal/mol

4) Atropine base decomposes with a rate constant of 0.016 s-1 at 40 oC. The energy of activation is 7.7 kcal/mol. Calculate the t90 at 25 oC.

seconds

5) The rate constant for the degradation of a drug following zero-order kinetics was determined to be 0.02 mg/mL-day. If the initial concentration of the drug was 500 mg/mL in a 20-mL package, determine the shelf-life. Assume that the shelf-life corresponds to the t90 value.

months

6) Drug A degrades by first-order kinetics. The data in the table below show the changing concentration of Drug A with time, in mg per 5 mL of solution. Calculate the first-order degradation rate constant, k. Time, months 0.25 0.38 0.50 0.60 0.76 0.90 Drug A Concentration, mg/ 5 mL of solution 200 145 100 78 50 36

months-1
4

7) Using the data for Problem #6, calculate the initial concentration of Drug A (i.e., the concentration at t = 0).

mg/5 mL

8) Using the data for Problem #6, calculate the degradation half-life for Drug A under these conditions.

days

9) Using the data for Problem #6, estimate the shelf-life for Drug A under these conditions. Assume the shelf-life corresponds to the t90 value.

months

Use the figure below to answer questions 10-14. The figure shows the pH-rate profile for the degradation of [Arg8]-vasopression (AVP) in aqueous solution at 50 oC. AVP is a peptide hormone with the amino acid sequence Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH2 [disulfide bridge (1-6)], and has been used to treat diabetes and other diseases. Note that the units of the y-axis are log (base-10) and not natural log. (Source: M. Bi, J. Singh, Fig. 2).

10) At what pH is AVP most stable?

11) What is the half-life for AVP degradation at pH 7 and 50 oC?

hours

12) What is the ratio of half-life for AVP degradation at pH 7 to the half-life for AVP degradation at pH 4?

13) The activation energy (Ea) for AVP degradation was measured to be 21.5 kcal/mol at pH 3.35. Calculate the shelf-life for AVP at 25 oC and pH 3.35, assuming that the t90 value represents the shelf-life.

years

14) The authors of the paper do not describe the chemical mechanisms of AVP degradation in detail. List two possible types of degradation reactions for this molecule.

1)________________________ 2)________________________

Use the figure below to answer questions 15-20. The figure shows the pH-rate profile for the hydrolysis of valacyclovir . Acyclovir is a nucleoside analog used to treat viral infections, but it has very low oral bioavailability (15-30%). Valacylovir is a prodrug of acyclovir designed to improve oral absorption. Note that commas in the values on the y-axis of the pH-rate profiles should be interpreted as decimal points.

15) One of the products of valacyclovir hydrolysis is the parent drug, acyclovir. What is the second hydrolysis product? Draw the structure below and write the name of this compound in the box.

16) What type of bond is hydrolyzed to convert valacyclovir to acyclovir?

17) At what pH is valacyclovir most stable?

10

18) What is the half-life for valacyclovir hydrolysis at pH 7.4? Since 7.4 is the pH of human blood, this half-life represents the time needed to convert valacyclovir to acyclovir once its in the bloodstream.

hours

19) What is the half-life for valacyclovir hydrolysis at pH 3.5? This is approximately the pH of the stomach contents. Both valacyclovir and acyclovir are given orally.

hours

11

20) The oral bioavailability of valacylovir is ~55%. This is better than acyclovir, but still disappointingly low. In the box below, offer a brief (1-2 sentence) explanation for the low oral bioavailability of valacyclovir.

12