Selaginella: features, morphology ,anatomy and reproduction.
Stabilization of Drugs against Degradation
1. Stabilization of Drugs against
Degradation
Presented By : Shreyaskumar Jitendra Patel
Enrolment No. : 101PHSPPC2122014
M.Sc Pharmaceutical Chemistry
Submitted To : Dr. Prajesh Prajapati
Asst. Professor, School of Pharmacy, NFSU
2. • The USP defines the stability of pharmaceutical products as "extent
to which a product remains within specified limits" and throughout its
period of storage and use (i.e. its shelf life) the same properties and
characteristics that it possessed at the time of its manufacturer.
What is Drug Stability ?
3. • Each active ingredient retains its chemical
integrity and labelled potency within the
specified limits
1. Chemical
• The original physical properties including
appearance, palatability, uniformity,
resolution and suspendability are retained.
2. Physical
Types of Stability
4. Types of Stability
• Original to microbial growth is written according to the
specific requirement anti microbial agents that are
present written effectiveness within the specified limits
3. Microbial
• The therapeutic effect remains unchanged
4. Therapeutic
• No significant increasing toxicity occurs.
5. Toxicological
5. • Provide evidence and how the quality of a drug substance or a drug product varies with time under
the influence of variety of environmental factor such as temperature humidity and light
• Establish the re-test period for the drugs after a self life for the drug product and recommended
storage condition
Why Stability ?
6. • To determine maximum expression date
or self life.
• To provide better safety to the patient.
• To provide better storage condition.
• To determine the packaging components.
• Together information during pre-
formation stage to produce a table
product.
Objective of the drug stability
7. • Chemical degradation lead to
lowering of drug concentration.
• Formation of toxic metabolites on
degradation.
• Instability earning to change in
physical appearance of the doses
form.
Reason to study Stability in Drug
Physical appearance of CMS-(high amylose content) based tablets with
different DS incubated in SGF for different time
8. • Pharmaceuticals should be stored under conditions favorable to greater drug stability.
• The temperature dependence of the rate of drug degradation indicates that
pharmaceuticals should be stored at low temperature if they lack sufficient stability at
normal temperatures.
• The exceptions to this rule are the occasional drugs on which freezing has an adverse
effect.
• It is also important to avoid oxygen and light by using suitable containers and packaging
in cases where these variables enhance drug degradation.
Stabilization of Drug Substances against Degradation
10. The degradation rate of drug substances is affected by various factors.
• For example, in a given formulation strategy, such factors as pH, ionic strength, and solvent
dielectric constant could be controlled so as to attain the lowest possible degradation rate for a
particular drug.
• Other molecules such as buffers and excipients, which can possibly interact with the drug directly
or act as general acid-base catalysts, nucleophilic or electrophilic catalysts etc., should be
excluded or their concentrations should be minimized.
• Other approaches include minimization of moisture, particularly freely mobile water present in
excipients, especially in solid-dosage-form formulations.
Stabilization of Drug Substances against Degradation
11. 1
• Stabilization by Modification of Molecular Structure of Drug
Substance
2
• Stabilization by Complex Formation
3
• Stabilization by Formation of Inclusion Complex with Cyclodextrin
Other Methods for Stabilization of Drug Substances
against Degradation
4
Addition of Stabilizers Such as Antioxidants and Stabilization through
the Use of Packaging
5
Stabilization by Incorporation into Liposome, Micelles or Emulsion
12. • Drug degradation rates depend on the
chemical structure of the drug.
• Most often, structure modifications are
performed to enhance activity or to have a
positive impact on the in vivo properties of
the drug. However, for drugs that are very
chemically unstable, development of more
stable analogs should be possible through
appropriate structure modifications.
1. Stabilization by Modification of Molecular
Structure of Drug Substance
An example of analog development to effect stabilization is the masking of reactive hydroxyl groups.
13. 1. Stabilization by Modification of Molecular
Structure of Drug Substance
(a) erythromycin (b) clarithromycin
14. • Degradation of erythromycin via 6,9-hemiketal
breakdown under acidic pH conditions is
inhibited by substituting a methoxy group for the
C-6 hydroxyl.
• For example, the acid stability of clarithromycin
is 340 times greater than that of erythromycin.
• Many studies have been reported on the
stabilization of drugs against enzymatic
degradation in vivo, such as the protection of
peptides from metabolism by modifying the N-
terminal with an ethyl group.
1. Stabilization by Modification of Molecular
Structure of Drug Substance
15. • Complex formation between drugs and excipients often leads to stabilization of drugs. The forces
involved in complex formation include van der Waals forces, dipole and dipole interactions,
hydrogen bonding, Coulomb forces, and hydrophobic interactions.
• The effect of complex formation on drug stability can often be described in terms of the processes
represented by this scheme.
If drug D forms a complex with ligand L, the complex (assuming a 1 : 1 interaction) can be defined by a
complexation constant K:
2. Stabilization by Complex Formation
16. The degree of stabilization will also depend on the relative amounts of free and complexed drug,
which in turn depends on the concentrations of D and L and the magnitude of K.
2. Stabilization by Complex Formation
[D-L] - represents the concentration of
the complex
[D]f - concentration of free or un-
complexed drug
[L]f - concentration of free ligand
Kf - rate constant for the degradation of
the drug in the absence of complexation
Kc - is the rate constant for the
degradation of the drug in its complexed
form.
17. The degree of stabilization will also depend on the relative amounts of free and complexed drug,
which in turn depends on the concentrations of D and L and the magnitude of K.
2. Stabilization by Complex Formation
The drug will be stabilized
by the presence of L if ???
or
Stabilization of esters such as benzocaine, procaine, and tetracaine by complex
formation with caffeine was reported in the 1950s.
The stabilization of drugs by caffeine is thought to result from the formation of
“stacking” complexes.
Thus, attack by water or hydroxide ion on the ester bonds of benzocaine is hindered
when the benzocaine molecules are sandwiched between caffeine molecules.
Similar stabilization by caffeine has been reported for base-catalyzed degradation of
riboflavin.
20. 3. Stabilization by the Formation of Inclusion
Complexes with Cyclodextrins
In the caffeine examples given above, the practicality is lost because of the non-inert nature of the ligand,
caffeine.
Recently, considerable interest has been generated in the use of cyclodextrins (CDs) to improve drug
stability.
Cyclodextrins are nonreducing cyclic oligosaccharides, consisting of six (α-(CD), seven (β-CD), or eight (γ-
CD) dextrose units.
Cyclodextrins have a “doughnut” shape, with the interior of the molecule being relatively hydrophobic and
the exterior being relatively hydrophilic. Because of their unique chemical structure, cyclodextrins are
capable of forming so-called “inclusion” complexes with many drug molecules.
22. 3. Stabilization by the Formation of Inclusion
Complexes with Cyclodextrins
Interaction of free drug molecules (Df) with the cavity of cyclodextrins. The
formation of an “inclusion” complex can lead to either stabilization of the drug or
catalysis of its breakdown.
23. 3. Stabilization by the Formation of Inclusion
Complexes with Cyclodextrins
If drug D is capable of undergoing chemical degradation in solution, protection of the molecule by
inclusion complexation with a cyclodextrin is often possible.
The natural cyclodextrins, α − , β −, and γ-CD, have been chemically modified either to effect stronger
complexation or to improve their safety. α-CD and β -CD cannot be used parenterally because of their
nephrotoxicity. Recently, a number of modified cyclodextrins, including 2-hydroxypropyl-β -cyclodextrin
(HP-β -CD) and sulfobutylether β-cyclodexhins [mainly (SBE)7M-β -CD, CaptisolR], have been tested. They
show better safety profiles than does β-CD.
The overall loss of drug in the presence of cyclodextrins can be defined by
24. 3. Stabilization by the Formation of Inclusion
Complexes with Cyclodextrins
Stabilization of prostacyclin and prostaglandins in solution and in the solid state by various CD derivatives
is well known.
Stabilization of prostacyclin by increasing concentrations of α-
CD (1), β -CD(2), and γ -CD (3) (pH 7.0, 15°C).
α-CD (1)
β -CD(2)
γ -CD (3)
25. 3. Stabilization by the Formation of Inclusion
Complexes with Cyclodextrins
Stabilization of a benzylpenicillin prodrug by HP-β-CD (pH 6.93, 40°C). HP-β-CD concentration: 1) 0% 2) 0.5% 3) 1%
1) 0%
2) 0.5%
3) 1%
26. 4. Stabilization by Incorporation into Liposome,
Micelles or Emulsion
• Entrapment of drug substances in liposomes and micelles can lead to changes in their stability.
• When entrapment reduces the degradation rate, it can be used as a method for stabilizing pharmaceuticals.
• Aspirin can be partially stabilized by incorporation in L- α - dimyristoylphosphatidylcholine (DMPC)-based
liposomes.
• Anesthetics such as procaine are also stabilized by incorporation in liposomes.
• Physostigmine salicylate in a phospholipid emulsion is stabilized through interaction with phospholipids at the oil
and water interface and through incorporation into the internal phase of the emulsion
• Glycerol, a viscosity-inducing agent, apparently stabilizes drug substances by inhibiting drug diffusion. Photolysis of
vitamin B12 is inhibited by addition of glycerol.
28. 5. Addition of Stabilizers Such as Antioxidants
and Stabilization through the Use of Packaging
• Positive methods for stabilizing pharmaceuticals, involving modification of the molecular structure or the
microscopic environment in which the drug is formulated, have been seen.
• On the other hand, the exclusion of some factors adversely affecting drug stability can also lead to the stabilization
of pharmaceuticals. Because oxygen, light, and moisture often enhance drug degradation as you know, various
methods for excluding these factors have been considered as means of stabilizing pharmaceuticals.
• Often, the effect of oxygen can be eliminated by the addition of antioxidants.
• Oxidation of lovastatin in aqueous solution is inhibited by antioxidants such as α-tocopherol and butylated
hydroxyanisole (BHA).
• The inhibition of the oxidation of cholecalciferol by α -tocopherol and ascorbic acid.
29. 5. Addition of Stabilizers Such as Antioxidants
and Stabilization through the Use of Packaging
• Positive methods for stabilizing pharmaceuticals, involving modification of the molecular structure or the
microscopic environment in which the drug is formulated, have been seen.
• On the other hand, the exclusion of some factors adversely affecting drug stability can also lead to the stabilization
of pharmaceuticals. Because oxygen, light, and moisture often enhance drug degradation as you know, various
methods for excluding these factors have been considered as means of stabilizing pharmaceuticals.
• Often, the effect of oxygen can be eliminated by the addition of antioxidants.
• Oxidation of lovastatin in aqueous solution is inhibited by antioxidants such as α-tocopherol and butylated
hydroxyanisole (BHA).
• The inhibition of the oxidation of cholecalciferol by α -tocopherol and ascorbic acid.
30. 5. Addition of Stabilizers Such as Antioxidants
and Stabilization through the Use of Packaging
• Pharmaceuticals are often stabilized by the utilization of packaging containing an antioxidant. For example, the
photooxidation of cianidanol in the solid state was inhibited by lowering the concentration of oxygen with the use
of an oxygen absorbent.
Stabilization of cianidanol against photodegradation
(light source: mercury lamp) in the solid state
by the use of an oxygen absorbent.
31. 5. Addition of Stabilizers Such as Antioxidants
and Stabilization through the Use of Packaging
• The use of photoprotective films generally eliminates the effect of light. A film coating containing oxybenzone
inhibited coloration and photolytic degradation of sulfisomidine tablets.
• The extent of inhibition depended on the concentration of the W absorber and the thickness of the film.
• Stabilization of other pharmaceuticals against photodegradation by the use of colorants has also been reported;
for example, daunorubicin in solution was stabilized by the addition of various colorants and ubidecarenone in a
dry emulsion was stabilized by the addition of α-(o-tolylazo)- β-naphthylamine.
• Various methods for protecting pharmaceuticals from the effect of moisture have been considered, with the use of
moisture-proof packaging and film coatings being the techniques most often utilized.
q.s – Quantum Satis – Latin Word – amount which is enough or this term is used when bringing up a volume or weight to the final measurement.
Erthromycin – Macrolide Antibiotic
Bacterial Infection – pneumonia, STDs, Bronchitis
Macrolide are the class of natural products that consists of a large macrocyclic lactone ring. Usually 14, 15 or 16 member ring/
Benzocaine – short term relieve pain from minor mouth problems, procaine – arthritis, cerebral atherosclerosis, Sexual Performance Problems etc – Local Anesthetic –Used in Pain Control Management
Nephrotoxicity – a rapid deterioration in the kidney function due to the toxic effect of medications and chemicals.
Prostacyclin analogs- used to treat pulmonary arterial hypertension
Benzylpenicillin – Peanut Butter Shot
Physostigmine salicylate – to treat glaucoma and the treatment of anticholinergic toxicity
Aspirin - NSAIDs
Physostigmine salicylate – to treat glaucoma and the treatment of anticholinergic toxicity
Aspirin - NSAIDs
Lovastatin – HMG CoA Reductase inhibitors – Statins – Lipid Lowering Medicines
Cholecalciferol – Vitamin D3
α-tocopherol – Vitamin E