Drug Excipient Interaction, Different Methods, Stability Testing. drug excipient Compatibility and Incompatibility, Goals of drug excipient compatibility Methods, Factors Influencing stability Testing, Significant changes that might occur during satability Analysis

1. DRUG EXCIPIENT INTERACTION, DIFFERENT METHODS, STABILITY TESTING.
( AS A PART OF PREFORMULATION)
PRESENTED BY
SHABANA S HUBBALL
M PHARM 1ST YEAR
DEPARTMENT OF PHARMACEUITCS

2.  DRUG EXCIPIENT INTERACTIONS
1. In order to develop and manufacture a medicine, three main components are considered drug,
excipients,and the manufacturing process the interaction between excipients and the other two
components or between two or more excipients.
2. Excipient interactions are a larger part of why medicines work
3. They can be either beneficial or detrimental and depends on the particular application.
4. Excipient interaction can have implications for drug stability, product manufacture, drug release
therapeutic activity etc.
5. Interaction between drugs and excipients can occur by means of several possible mechanism
which includes adsorption, complexation, chemical interaction, pH effects, enteric formulation etc.
6. Resulting in drug products with desired or undesired products.

3. • Drug excipient compatibility
1. The successful formulations of a stable and effective dosage form depends not only on the
active Pharmaceutical ingredient but also and the careful selection of excipients.
2. The proper selection of excipients is vital in the design of a quality drug product.
3. The selection of the excipients and their concentration in a formulation is based not only on
their functionality but also on the compatibility.
4. An incompatibility may result in changes in physical, chemical, microbiological or therapeutic
properties of the dosage form.
5. Drug excipient compatibility studies are conducted mainly to predict the potential
incompatibility.

4. • Drug excipients incompatibility
 An incompatibility in the dosage form can result in any one of the following changes .
 Change in organoleptic properties
 Change in dissolution performance
 Physical form conversion
 An decrease in potency
 An increase in degradation products.

5.  IMPORTANCE OF DRUG-EXCIPIENT COMPATIBILITY STUDIES
1. It maximizes the stability of a dosage form,.
2. It bridges drug discovery and development.
3. It is essential investigational new drug submission (IND).
4. It helps to avoid surprise problems during formulation processes.

6.  Goals of Drug-Excipient compatibility studies
1. To find out how compatible an excipient is with Active Pharmaceutical Ingredient
(API) or candidate drug molecules.
2. To find out the excipient that stabilizes an unstable API.
3. To assign a relative risk level to each excipient.
4. To design and develop selective and stability indicating analytical methods to
determine their impurities

7.  DIFFERENT METHODS OF DRUG EXCIPIENTS INTERACTION ARE
A. PHYSICAL INTERACTION
B. CHEMICAL INTERACTION
C. PHYSIOLOGICAL INTERACTION

8. A. PHYSICAL INTERACTION:
1. These type of interaction are quite common but are very difficult to detect in dosage forms
drug substances and excipients interact with out undergoing changes involving breaking of
formation of new bonds.
2. The components of the drug product retain their chemical structure but undergo changes with
alter the physical properties.
3. Physical interactions may result in changes in dosage uniformity, colour, odour, flow
properties, solubility, sedimentation rate, dissolution rate etc.
4. Incompatibilities are assessed by physically observing the test samples.
5. Physical interactions can be either beneficial or detrimental to the product performance
depending on its application.

9.  BENEFITS OF PHYSICAL DRUG-EXCIPIENT INTERACTIONS
1. Improves bioavailability of sparingly water-soluble drugs: The bioavailability of sparingly water-
soluble drugs can be enhanced using complexing agents e.g., complexation of cyclodextrin with
ursodeoxycholic acid increases the rate and extent of drug dissolution which in turn increases
the bioavailability of the drug substance.
2. Increases surface area of drugs available for dissolution: Adsorption of drugs on excipient
surface can increase the surface area of the drug available for dissolution. Thus, an increase in
bioavailability of drug substance. E.g., formulation of indomethacin using kaolin as adsorbent
increases its bioavailability as a result of increased dissolution rate.
3. Improves dissolution rate and bioavailability of hydrophobic drugs: Physical interactions of
drugs with excipient improve the dissolution rate and bioavailability of hydrophobic drugs. E.g.,
improved dissolution rates of drugs like piroxicam, norfloxacin, nifedipine and ibuprofen were
achieved when these drugs were formulated into solid dispersions using polyethylene glycol of
different molecular weights.

10.  Detrimental effects of physical drug-excipient interactions
1. Decreases dissolution and absorption rates of drug substances due to the formation of insoluble
complexes e.g., tetracycline forms an insoluble complex with calcium carbonate leading to
slower dissolution and decreased absorption in the gastrointestinal tract. Formulation of
chlorpromazine with polysorbate 80 and sodium lauryl sulphate decreased membrane
permeability of the drug.
2. Reduces bioavailability of drugs available for dissolution: Adsorption of drugs on excipient
surface can also lead to reduced bioavailability as the drug is not available for dissolution. E.g.,
the marked reduction in the antibacterial activity of cetyl pyridinium chloride cations in tablets
containing cetyl pyridinium chloride is due to the adsorption of cetyl pyridinium chloride on the
surface of magnesium stearate which acts as a lubricant.
3. Slow dissolution of drugs: Ion interactions can result in slow dissolution of drugs. E.g., solid
dispersion product formed due to interactions between povidone and stearic acid in a capsule
showed slow dissolution of the drugs.

11. B) Chemical drug-excipient interactions
1. This involves the interaction of drug substance and excipient through chemical degradation
pathway. The formulation undergoes a chemical reaction in which the constituent atoms are
rearranged via bond breakage and bond formation to produce an unstable chemical entity.
Generally, chemical interactions have a deleterious effect on the formulation hence; such kind of
interactions must be avoided. Chemical interactions can be in the form of hydrolysis, oxidation,
racemization, polymerization, Maillard reactions, photolysis etc., and changes in the study
samples are analyzed by a chromatographic-based assessment of potency and formation of
degradants or by any other analytical method depending on the nature of the candidate drug
molecule, available literature and the goals of the study. Some examples of chemical drug-
excipient interactions include
2. Inhibition of diclofenac sodium release from matrix tablet by polymer chitosan at low pH. This
occurs possibly via formation of ionic complex between diclofenac sodium and ionized cationic
polymer.
3. Oxidation of diethylstilbestrol to the peroxide and conjugated quinone degradation products by
Silicon dioxide which acts as a catalyst.

12. C) PHYSIOLOGICAL/BIOPHARMACEUTICAL DRUG-EXCIPIENT
INTERACTIONS
1. Interactions that occur after the drug product has been administered to the patient. These
interactions are similar to physical interactions but differ in the sense that
2. The interaction is between the medicine (drug substance and excipients) and the body fluids.
3. The interactions have the tendency to influence the rate of absorption of the drug.
4. All excipients interact in a physiological sense when they are administered as part of a dosage
form. They are included in a formulation specifically because they interact with the physiological
fluids and function in certain ways e.g., disintegrants in immediate release tablets and capsule
formulations. On the other hand, physiological interactions can be detrimental to the patient.
Examples of such interactions include.

13. Examples of physiological interactions include
1. Premature breakdown of enteric coat – Enteric coating polymers e.g., cellulose acetate
phthalate and hydroxyl propyl cellulose acetate phthalate, dissolve prematurely in the
stomach in the presence of antacids or drugs that cause increase in the pH of the stomach.
This results in premature release of active pharmaceutical ingredient in stomach itself, which
case results in degradation of drug in stomach e.g., pro-drugs or side effects like gastric
bleeding as in the case of NSAIDs.
2. Interactions due to adjunct therapy– A classic biopharmaceutical incompatibility is the
interaction between tetracycline antibiotics and antacids containing aluminum, calcium,
magnesium, bismuth and zinc ions. The tetracycline antibiotics chelates with these metallic
ions to form complexes which only are not poorly absorbed, but also have reduced
antibacterial effects.
3. Increase in gastrointestinal motility – Certain excipients such as sorbitol and xylitol have the
tendency to increase gastrointestinal motility, thus reducing the available time for absorption
of drugs like metoprolol. The effect is very much dependent on the amount of the excipient
administered at one time. Polyethylene glycol 400 has also been reported

14.  STABILITY TESTING
• DEFINATION
It is a method to check the quality and how the system or software behaves in different
environmental parameters like temp, voltage etc. In the pharmaceutical field, how well a
product retains its quality over the life span of the product.

15.  WHY STABILITY ANALYSIS/ TESTING?
1. To generate useful information on how environmental factors e.g., temperature, humidity, light
etc. influence the quality of drug products over time.
2. To establish the how physical, chemical and microbiological changes influence the
effectiveness, safety and stability of the final drug product.
3. To recommend storage conditions, establish a retest period, and shelf life of drug products.

16.  FACTORS INFLUENCING DRUG STABILITY
• Temperature or thermal effect
• Moisture and relative humidity
• Light and radiation energy
• pH
• Presence of reacting solvents
• Order of reaction
• Microorganisms
• Chemical nature of the drug or excipient
• Ionic strength
• General acid-base catalysis
• Presence of trace metals, oxygen and oxidizing agents.

17.  SIGNIFICANT CHANGES THAT MIGHT OCCUR DURING
STABILITY ANALYSIS
1. Physical changes – changes in the physical appearance of the drug product,
melting point, clarity and color of solutions, crystal modification (polymorphism)
and particle size etc.
2. Chemical changes – increased degradation and decrease API (Active
Pharmaceutical Ingredient) assay
3. Microbial changes – increased microbial load/ microbial contamination.

18.  STABILITY EVALUATION FOR DIFFERENT FORMULATION
1. TABLETS
 Odour
 Colour
 Assay
 Degradation
 Products
 Dissolution
 Moisture
 Hardness or friability

19. 2. CAPSULES
 Appearance
 Colour
 Odour
 Assay
 Degradation products
 Dissolution
 Moisture and microbial content

20. 3. EMULSION
 Appearance
 Colour
 Odour
 Assay
 pH, viscosity, microbial limits
 Preservative content, and mean size and distribution of dispersed
globules.

21. 4. ORAL SOLUTION AND SUSPENSIONS
 Additionally for suspension, rheological properties
 Mean size and distribution of particles should be considered
 Oral powders for reconstitution time.
 Moisture and reconstitution time .

22. 5. METERED DOSE INHALATION AND NASAL AEROSOLS
 Appearance
 Dose content uniformity
 Aerodynamic particle size distribution
 Microscopic evaluation
 Water content
 Leak rate
 Microbial limits

23. 7. TOPICAL AND OPTHALMIC SOLUTION
 Topical preparations
 Clarity, colour ,odour ,pH resuspendability, consistency
 Viscosity
 Preservative and anti oxidant content
 Sterility
 Evaluation of ophthalmic
• Sterility
• Particulate matter and extractable

24. 8. SUPPOSITORIES
 Softening range, dissolution
 Microbial limits
9.SMALL VOLUME PARENTERALS & LARGE VOLUME PARENTERALS
 Particulate matter,
 pH, sterility
 and pyrogen or endotoxin

25. 9. TRANSDERMAL PATCHES
In vitro release rates
 Leakage
 Sterility
 Peel and adhesive forces
 The drug release rate

26. 10. FREEZE DRIED PRODUCTS
Appearance of both freeze dried and its reconstituted, product, assay,
 Degradation product pH water content and rate of solution

27. THANKYOU