Kinetics and Stability Studies: Stability of Suspensions II Flashcards
Dr. Ilomuamya
Using adequate chemical equations, briefly discuss hydrolysis as a factor affecting the chemical stability of drug formulations..
This is the breaking of a molecular bond by reaction with water which is a common pharmaceutical ingredient or contaminant. Hydrolysis is the most common cause of
chemical degradation.
Molecules containing the ester group hydrolyse to produce
a carboxylic acid and an alcohol.
The carbon of the carboxyl group of esters is relatively electron deficient
due to bond polarisation caused by the adjacent oxygen atoms. This promotes nucleophilic attack by water.
Equation: [Use equation of hydrolysis of aspirin. Learn structures.]
Why is the antimicrobial drug
Chloramphenicol relatively susceptible to hydrolysis
compared to other amides?
This is due to a high
degree of polarization of the amide bond by the highly electronegative chlorine substituents
which are adjacent.
Eye drop preparations of chloramphenicol therefore require storage in a refrigerator.
[Learn structure]
With a suitable example and equation, briefly discuss oxidation as a factor affecting the chemical stability of drug formulations.
Oxidation reactions involve an increase in the number of carbon-to-oxygen bonds in a molecule or a reduction in the number of carbon-to-hydrogen bonds.
They are responsible for deterioration of vegetables which may be used in pharmaceutical products as solvents or emollients as in emulsions and creams
Oxidation taking place at ambient temperature involving molecular oxygen is auto-oxidation. Most such reactions involve free radicals.
Example: [Equation of oxidation of ascorbic acid to dehydroascorbic acid]
** Free radicals are chemical species which possess an unpaired electron.
What are the three main phases involved in free radical oxidation?
- Initiation Phase: results in the formation of a low concentration of free radicals.
- Propagation Phase:
concentration of free radicals increases rapidly. - Termination phase: The rate of the reaction decreases as the availability of reactants (like oxygen or the drug) diminishes. Free radicals combine with each other to form stable, unreactive end products
The stable reaction products formed in
vegetables include carboxylic
acids which are responsible for
the rancid smell formed when
oil deteriorates.
With a suitable example, briefly discuss dimerization and polymerization as factors affecting the chemical stability of drug formulations.
Reaction of a drug molecule with another molecule of the same drug may result in the formation of a dimer or polymer.
Example: Amoxicillin also undergoes dimerization by nucleophilic attack by the amino group on the beta lactam ring, especially in concentrated solutions. This reaction can continue to produce a trimer and tetramer.
Example: Polymerization is a major mechanism of degradation of the
disinfectant glutaraldehyde. Its disinfectant activity is optimal at a slightly alkaline pH but at this pH, it is subject to polymerization.
What is epimerization?
Provide one example.
Epimerization is a type of racemization that occurs at one chiral center in a molecule that has more than one chiral center, leading to the formation of epimers.
Example: Tetracycline forms 4 epi-tetracycline
epimer which is not active against microbes and is more toxic than tetracycline.
Providing suitable examples, briefly discuss photodegradation as a factor affecting the chemical stability of drug formulations.
Photodegradation is the process by which a substance is chemically broken down or altered due to exposure to light, particularly ultraviolet (UV) light.
Many drugs are susceptible to photodegradation, which can result in reduced potency and the formation of harmful degradation products.
(The 300-400nm
wavelengths, though not of practical concern, tend to be the most damaging.)
Example: The photodegradation of chloroquine and primaquine yields various products.
Briefly discuss conformation of proteins as a factor affecting the chemical stability of drug formulations.
The therapeutic effect of protein based drugs
depends on the three-dimensional structure of the molecule.
Changes to this on storage due to effects of temperature of pH result in a reduction of the proteins
efficacy.
Give an example of chemical incompatibilities of formulation components affecting the chemical stability of a drug formulation
Parabens (hydroxybenzoate esters) undergo
transesterification reactions with sugars and sugar alcohols which may be present in formulations as sweetening agents.
Methyl paraben reacts with sorbitol to produce sorbitol hydroxybenzoate esters.
Briefly discuss enzymatic decomposition as a factor affecting the chemical stability of drug formulations.
Enzymatic decomposition refers to the breakdown or degradation of drugs and pharmaceutical compounds catalyzed by enzymes in biological systems.
Due to their small size, linear permutation and lack of tertiary structure, peptide drugs are easily subject to rapid degradation or loss in vivo, thus resulting in a short half-life and
reduced therapeutic efficacy
What are the anti-degradation strategies used in small-peptide drugs?
- The use of enantiomeric or non-natural amino acids (AAs) (e.g., L-AAs
replacement with D-AAs) - Molecular conjugation: chemical conjugation of a peptide with another macromolecule can provide significant protective effects
against degradation.
e.g.,
i. PEG-peptide conjugates improve multiple physiochemical and pharmacokinetic performance.
ii. Conjugation with plasma proteins, such as albumin. Due to its
chemical composition and large size, albumin has a low renal
clearance, thus prolonging the half-life of the conjugated peptide. e.g. Albiglutide (Tanzeum®) is an albumin-peptide conjugate used to treat type-2 diabetes. - Drug delivery devices: often
manufactured from nonbiodegradable materials (e.g., alloys), provide another strategy for protecting and delivering small therapeutic peptides
e.g. DUROS® is a tube-shaped drug delivery device that is made from a titanium alloy containing a drug reservoir chamber
and an orifice from which the peptide is released.
- Lupron® is used to treat prostate cancer - Modification of C- or N-terminus: the C- or/and N-terminus of
peptide chain is biochemically modified, thus preventing interactions with
proteases . - Encapsulation in exosomes or liposomes:
- Nanoparticles / microparticles: Due to their size, high ratio of surface area to volume, high bioavailability and high stability, nanoparticles are a promising transport platform for facilitating drug delivery.
What are the components of an insulin pump?
i. An insulin reservoir:
capable of holding sufficient insulin for a few days
ii. A catheter that is
inserted subcutaneously for insulin delivery
iii. A battery
iv. A processor that adjusts the frequency and amount of insulin delivered
Mention 5 small therapeutic peptides that are currently used in clinical therapy for major non-infection diseases.
- Insulin (Humulin R®): To treat diabetes.
- Exenatide (Byetta®): GLP-1 receptor agonist for treating type-2 diabetes
- Lixisenatide (Adlyxin®): GLP-1 receptor agonist for treating type-2 diabetes
- Abarelix (Plenaxis®): Gonadotropin-releasing hormone receptor antagonist to treat prostate cancer
- Nesiritide (Natrecor®): recombinant version of human B-type natriuretic peptide, used for patients with decompressed heart failure.
Mention 3 classes of formulation additives that are added internally to achieve both physical stability and dissolution performance.
(i) A second polymer, to form a ternary drug-polymer–polymer ASD,
(ii) counterions, to facilitate in situ salt formation
(iii) surfactants/ preservatives
Explain why lixisenatide, as a peptide, is protected against degradation.
Because lixisenatide C-terminus is amidated, with an amide group instead of a carboxyl group.
