Presentation

Effect of chemical factors on drug

stability

Subject:
Drug stability and chemical kinetics
Submitted to: Dr. Sajid Akash
Submitted by: Group 5
Group members
• Qudsia rehman 606
• Mutayaba 608
• Noor ul huda 613
 Introduction

• Definition
▫ Drug stability means the ability of the pharmaceutical
dosage form to maintain the physical, chemical,
therapeutic and microbial properties during the time of
storage and usage by the patient.
• The chemical stability of drug products involves
the assessment of the chemical integrity and labeled
potency of all the ingredients and that any change
should be within the specified limits.
Chemical Degradation Reactions

The major modes of drug degradation are:

• Hydrolysis
• Isomerization
• Oxidation
• Decarboxylation
• Elimination
• Dimerization
• Epimerization
• Dehydrogenation
• Dehalogenation
Hydrolysis
• Hydrolytic degradation in aqueous solution and in liquid dosage forms is
among the most common reactions destabilizing the drugs that contain
ester, amide, imide, carbamate, lactone, nitrile and carbohydrate groups.

• Drugs susceptible to acid and/or alkaline hydrolysis

• aspirin
• paracetamol,
• sulfacetamide,
• procaine,
• riboflavin,
• Chloramphenicol
• Cephalosporins e.t.c.
• The pH of the medium plays an important role in the hydrolysis of drugs
Hydrolysis of Esters

• The ester compounds undergo hydrolysis through

nucleophilic attack of water or OH ions on the ester
group.
• Acetylsalicylic acid (Aspirin)
Hydrolysis of Amides

• Compounds containing an amide bond are less

susceptible to hydrolysis compared with those
containing an ester bond. This is because of the fact
that the carbonyl carbon of the amide bond has a
lower electrophilic character.
• Paracetamol
Isomerisation
• Isomerization is a degradation process in which a
drug degrades to form a product with an identical
chemical formula (i.e., isomers).
• Isomers have the same chemical composition but a
different configuration or structure and possess
different physicochemical properties
Types

• Constitutional isomers are also called structural or

positional isomers. Theses are molecules with same
atomic composition but different bonding arrangements
between atoms.

• They are categorized into:

Chain isomers
Position isomers
Functional isomers
Metamerism
Tautomerism
Ring chain isomers
Example

• Catechol, resorcinol, and hydroquinone

• same atomic compositions (C6H6O2), but different
bonding arrangements of atoms
Tautomerism

• Tautomers are also structural isomers but they are

readily interconverted by a chemical reaction called
tautomerization.
• Pilocarpine
Types

• Configurational isomers are defined as molecules with

identical atomic composition and bonding arrangements but
with different orientation of atoms in the space. These
different orientations cannot interconvert freely by bond
rotation.
• It is divided into two types
1. Optical
i. Enantiomers
ii. Diasteromers
2. Geometrical
Example

• Premethin
Geometric Isomers of 3-
methylfentanyl
Types

• Conformational isomers are different by relative

spatial arrangements of atoms that results from
rotation about sigma bonds. Thus, unlike
configurational isomers, conformers are
interconverting stereoisomers of a single compound
Photodegradation:
• The process by which light- sensitive drugs or
excipient molecules are chemically degraded by
light: room light or sunlight.
• Photolysis sources
• Emitting in the 290–800 nm region
• Absorption of light at characteristic wavelength
cause increase in energy which can cause
decomposition.
Spectral Regions of the UV, Visible,
and Solar Radiation.
• .The spectral regions of the UV, visible, and solar
light involved in the photochemical reactions are as
follows:
• UVA: 320–400 nm.
• UVB: 290–320 nm.
• UVC: 200–290 nm.
• Visible: 400–700 nm.
• Solar: including UVA, UVB, and visible ranges. The
majority of the photochemical reactions occur with
the help of the UVA, UVB, or visible light.
• Photostability studies of drugs and drug
products are an integral part of the product
development process in the pharmaceutical
industry.
• Photoaddition (e.g., riboflavin)
• Photoaquation (e.g., cyanocobalamin)
• Photocyclization (e.g., meclofenamic acid)
• Photodealkylation (e.g., chloroquine)
• Photodecarboxylation (e.g., amino acids)
• Photodehalogenation (e.g., norfloxacin)
• Photodehydrogenation (e.g., nifedipine)
• Photodimerization (e.g., primaquine)
• Photoelimination (e.g., mefloquine)
• Photoinduced hydrolysis (e.g., sulfacetamide)
• Photoisomerization (e.g., aztreonam)
• Photooxidation (e.g., benzaldehyde)
• Photoinduced rearrangement (e.g.,
benzydamine)
• Photoreduction (e.g., riboflavin)
• Photoinduced ring cleavage (e.g., norfloxacin)
• In some of the photodegradation reactions, more
than one pathway may be involved; for example,
the hydrolysis of sulfacetamide is followed by
oxidation, the reduction of riboflavin is followed
by oxidation, the oxidation of furosemide is
followed by reduction.
Example:
• Photochemical stability of flunitrazepam
• Both in light and dark conditions
• After 8 hours of storage:
• under light : drop in the measured concentration
more than 60% occurred
• in the dark : no such change was noted
Oxidation:
• Oxidation is a loss of electrons or an increase in
the oxidation state.
• Reduced form Oxidized form + ne-
• It involves most often, increase in the number of
carbon to oxygen bonds in a molecule or
reduction of C-H bonds.
• Oxidation of organic compounds occurs
primarily via one of three mechanisms:
• Nucleophilic/electrophilic processes (mediated
by peroxides).
• Electron transfer reactions (via catalysis by
transition metal such as Cu ions).
• Free radical processes (autoxidation)
• A single free-radical can cause oxidation of many
drug molecules.
Example:
• Ascorbic acid (vitamin C)
• Many drugs are susceptible to oxidation and
undergo degradation in solid or liquid dosage
forms in the presence of oxygen during
processing or storage.
• Examples of these drugs include :
• 5-aminosalicylic acid, ascorbic acid, captopril,
epinephrine, hydroquinine, hydrocortisone, 6-
mercaptopurine, methyldopa, morphine,
phenylbutuzone, prednisolone, promethazine,
spironolactone, tetrazepam, vitamin A.
Decarboxylation:

• Removal of carbon dioxide group from a

compound is called as decarboxylation .
• Uncommon phenomenon
Example:
• 4-aminosalicylic acid which after
decarboxylation , in aqeous medium is
converted into 3-aminophenol.
pH and Drug Stability
• pH is one of the most important factors affecting the stability of a drug product.
• The effect of pH on degradation rate can be explained
by the catalytic effects that hydronium or hydroxide
ions can have on various chemical reactions.
• Just 1 pH unit shift will cause 10 folds change in rate
constant.
• Therefore when drugs are formulated in solution it is
essential to construct pH versus rate profile so thatu
optimum pH for stability can be located.
pH Rate Profile
• The pH-rate profile is a plot of the degradation rates vs pH values and is used for
visual comparisons.
• pH profiles are important and can lead to the establishment of the best buffer to use
in the formulation and/or the optimal pH range to obtain for the final preparation.
• The stability of solutions should include the study of pH changes, especially when
the active ingredients are soluble salts of insoluble acids or bases.
Contd…
• To develop a pH-Rate profile, it is important to develop stability-indicating assays
for the intact drug at the various pH values to be studied.
• Buffer solutions are prepared at the different pH values to be studied.
• A known concentration of the active drug in the various pH buffers is prepared and
initial samples are taken, followed by samples at defined time periods that are then
analyzed.
Drug-Excipient and Drug-Drug
Interactions
• The role that excipients play in drug stability has
been extensively reported. Examples include the
stabilizing effect of sugars on the degradation of
ascorbic acid in aqueous solutions
• the accelerating effect of talc on the hydrolysis of
thiamine hydrochloride powders.
Drug-Excipient and Drug-Drug
Interactions
• Reaction of bisulfite as anti oxidant.
• Reaction of amines with reducing sugars
• Presence of metals
• Presence of surfactant such as CTAB.
• Packaging materials