M.Pharm Pharmaceutics 1 sem

1. Drug Excipient interaction - different methods ,
kinetics of stability , stability testing .
Prepared By :- Arjun S.Dhawale
M.Pharm 1yr Pharmaceutics
Kamla Nehru College of Pharmacy
Butibori , Nagpur .

2. Content :-
1 - Introduction .
2 - Drug execipient interaction .
3 - Different Methods .
4 - Kinetics of stability .
5 - Stability testing .

3. Introduction :-
Excipients play important role in formulating a dosage form .
These are ingredients which along with active
pharmaceutical ingredients make up the dosage
forms.Excipients act as protective agents , bulking agents
and can also be used to improve bioavailability of drug .

4. Excipient
An excipient is an inactive substance formulated alongside the active ingredient of a medication
, for the purpose of bulking-up formulations that contain potent active ingredients .
The resultant biological , chemical and physical properties of the drug product are directly
affected by the excipient chosen , their concentration and interactions with API :
1-Consistency of drug release and bioavailability .
2-Stability including protection from degradation .
3-Ease of administration to the target patient population by the intended route .

5. Ideal property of Excipient
1-No interaction with drug .
2-Cost effective .
3-Pharmacologically inert .
4-Stable for handling .
5-Feasible .

6. Excipient are inactive ingredients used as carriers for the
active ingredients in a pharmaceutical product . These may
be classified into the following categories :
1-Anti-Adherents 8-Colours
2-Binders 9-Fillers
3-Disintegrants 10-Buffering agents
4-Preservatives 11-Chelating agents
5-Sweeteners 12-Flavours
6-Lubricants 13-Surfactants
7-Glidants 14-Anti-Oxidant

7. Drug excipient interaction
In pharmaceutical dosage forms the active pharmaceutical
ingredients are in intimate contact with the excipient which
are greate quantity excipient and drug may have certain
incompatibility which lead to drug excipient interaction.

8. Types of drug excipien interactions:-
1-Physical interactions.
2-Chemical interactions.
3-Biopharmaceutical interactions.
4-Excipient - Excipient interactions.

9. 1 - Physical Interactions.
Physical interactions alter the rate of dissolution , dosage
uinformity , etc. Physical interactions do not involve
chemical changes thus permitting the components in the
formulation to retain their molecular structure . Physical
interactions are difficult to detect .
Eg:- Complexation
Binds with drug to form complex , Which causes slower
dissolution .

10. 2 - Chemical interactions
Active pharmaceutical ingredients and exciepients react
with each other to form unstable compounds .
Eg:-
1-Hydrolysis
2-Oxidation
3-Photolysis
4-Isomerization
5-Polymerization

11. 3 - Biopharmaceutical interactions
These are the interaction observed after admission of the
medication . Interaction within the body is between
medicine and body fluids which influence the rate of
absorption . All excipient physiological way when they are
administered along with active pharmaceutical ingredients .
Eg:-
1-Premature breakdown of enteric coat .
2-Increase in gastrointestinal motility .

12. 4 - Excipient - Excipient interactions .
Excipient - Excipient interaction through observed very
rarely . There are prime importance in determining the
stability of the dosage forms excipient - excipient
interactions can be undesirable as well as some
interactions are used in the formulations to get the desired
product attributes .
Eg:-If improper addition of electrolyte such as Ca++ ion in
suspension containing (NaCMC) sodium carboxymethyl
cellulose which will cause of formation of CaCMC.

13. Different methods to detect drug - excipient compatibility .
1. Thermal methods of analysis:-
i. DSC(Differential Scanning Calorimetry)
ii. DTA( Differential Thermal Analysis)
iii. TGA(Thermogravimetric Analysis)
iv. Isothermal microcalorimetry
v. Hot stage microscopy
2. Spectroscopic technique:-
i. FT-IR Spectroscopy(Vibrational Spectroscopy)
ii. Pxrd(Powder X-Ray Diffraction)
iii. SSNMR( Solid-State Nuclear Magnetic Resonance Spectroscopy)
3. Chromatography:-
i. TLC/HPTLC(Thin-Layer Chromatography or High-Performance TLC)
ii. HPLC(High-Performance Liquid Chromatography)
4. Microscopical technique:-
i. Scanning electron microscopy
5. Accelerated stability study
6. Miscellaneous
i. Radiolabeled techniques
ii. Vapour pressure osmometry

14. 1 - Thermal Methods of Analysis :-
These techniques vary in their working principles, sensitivity
of the analysis, stressapplied to the sample, analysis time,
and required sample amount for the analysis.Furthermore,
each of the methods has its advantages and
disadvantages. Some of themhave poor predictive value,
whereas others are time-consuming methods.

15. ->(DSC)Differential Scanning Calorimetry
DSC is a widely used rapid thermal analysis technique using a small amount of sampleto
predict any physicochemical interaction between drug and excipients involving thermalchanges.
A thermogram of API is compared with the curve obtained from the physicalmixture of API and
excipient in a 1:1 ratio to maximize the possibility of observing aninteraction. It is assumed that
the thermal properties (melting point, change in enthalpy,etc.) of blends are the sum of the
individual components if the components are compatiblewith each other.In a DSC thermogram,
the disappearance, appearance, shift of DSC peakor changes in the expected enthalpies, or a
significant shift in the melting of the compo-nents represent incompatibility. However, small
changes in peak height, shape, and widthmay be due to probable changes in the mixture
geometry.

17. ->(DTA)Differential Thermal Analysis
Similar to DSC, DTA has been used to determine solid state incompatibilities for the last five
decades. DTA and DSC are similar in many aspects, and comparable thermal events can be
observed in both cases . Experimental simplicity, rapid measurement, and requirement of a
small quantity of sample are the major attractions of this technique for its use in pharmaceutical
incompatibility determination . As discussed, DTA is also used to measure the melting point as
well as the heat of fusion, similar to DSC . However, DTA differs in many aspects with DSC,
including the determination of temperature difference in DTA, while DSC measures enthalpy
change; DTA is more robust and an older technique in incompatibility determination than DSC;
DSC can be considered as an upgraded version of DTA, and thus DSC is more sensitive .

18. ->(TGA)Thermogravimetric Analysis
TGA is used to determine the composition of a material, and also to determine the thermal
stability. Therefore, the loss/gain, i.e., change in weight/mass and also the rate of such change
as a function of temperature, time, and atmosphere can be measured. An increase of weight or
mass may occur due to decomposition, reduction, evaporation, or desorption, whereas a
decrease in weight can result due to oxidation and absorption. Thus, characterization of material
can easily be determined if it exhibits a change in weight due to physical or chemical interaction
. TGA could provide several pieces of information on the components tested, including thermal
stability, a composition of the complex mixture, oxidative potential, effect of corrosive/reactive
environment, lifetime estimation of the test sample, decomposition characteristics, volatile and
moisture content.

19. ->Isothermal Microcalorimetry
Isothermal microcalorimetry is also considered to be one of the important tools in the
determination of solid-state pharmaceutical incompatibilities. This technique is 10,000
times more sensitive than the traditional DSC and allows detection of any incompatible
reactions at more pertinent temperatures, thus improving the probability of effective
extrapolation. This isothermal microcalorimetry can be employed to study degradation kinetics
of drugs in solid state and in solution.

20. ->Hot Stage Microscopy (HSM)
HSM is considered to be a versatile tool for envisaging thermal events by DSC and TGA, and
also for the screening of solid-state interactions. It is the thermal analysis technique that
combines the usefulness of thermal analysis together with the microscopic view to allow
characterization of bulk drugs, along with its crystal and hydrates . Although the previous
thermal methods were efficient, the involvement of HSM studies further complements the
outcome and usefulness of interaction studies . Visualization of thermal events on the mixture of
components could make HSM an efficient method to interpret certain erroneous explanations of
DSC. Thus visualization could enable a distinction between solid-state interaction and
incompatibilities. Another great advantage of this method is that it requires a very small
quantity of sample.

21. 2 - Spectroscopic Technique
->Vibrational Spectroscopy(FT-IR)
Vibrational spectroscopy has immense importance as an important tool in the pharmaceutical
application, where this spectroscopy technique encompasses Fourier Transform infrared (FT
IR), Raman and near-infrared spectroscopy. These techniques are sensitive to the chemical
structure of the compound and to the environment, where the bond vibrations are measured as
an analyzing parameter . Thus, the changing of vibration can help in the determination of solid-
state characterization behavior of API and also as a potential probe to determine intermolecular
interaction among different ingredients . Therefore, any pharmaceutical interaction type,
including dehydration or hydrate formation, desalting, morphological changes, or interchange
between amorphous and crystalline can easily be identified by this technique.

22. ->Powder X-Ray Diffraction
Among the methods for physiological characterization of solid pharmaceutical materials,
PXRD plays a pivotal role. Such a nondestructive nature and preparation of a unique
pattern for the crystalline phase during characterization is essential to ensure the reproducibility
of the manufacturing process . A direct measurement of crystalline material is plotted, where X-
ray diffraction intensity is plotted against diffraction angular parameter . A compatibility study
report has been depicted in represents X-ray diffractograms of ketoprofen, polyvinylpyrrolidone,
and a mixture of both, and represents ketoprofen, magnesium stearate, and a mixture
of both . Differences in peak, i.e., disappearance or less intensified peaks, of the mixture with
that of the individual components indicates the presence of interaction
between the components .

23. ->Solid-State Nuclear Magnetic Resonance Spectroscopy
ssNMR has shown immense potential as a tool in the field of pharmaceutical sciences
for determination of pharmaceutical solids quantitatively and qualitatively. Apart from
this, the ssNMR technique could guide in compound structure and conformation, assigning
resonance, analyzing molecular motion, and in the measurement of internuclear distances .
Thus, ssNMR is a highly selective technique that provides an idea of chemical bonding and
composition of the chemical compound. It is a highly selective technique where interference by
the excipients in the analyzing method is limited. In contrast to PXRD, this technique could aid
in the detection of the mixture components of crystalline and amorphous solids. It could also
analyze the signs of any incompatibilities between drug and excipient in the solid-state via
deviations in the chemical shifts at the interacting carbon atom due to changes in chemical
shifts . Besides its advantages over other techniques, it is restricted due to its lengthier data
acquisition process, and also due to the complex outcome interpretations.
.

24. 3 - Chromatography
->Thin-Layer Chromatography or High-Performance TLC (HPTLC)
This technique is important to quantitate the incompatibilities, and evidence of interaction and
thus degradation products can be clearly indicated. The structure of the degradants or
prediction of a possible mechanism of the interaction is not possible via this technique. A
separate spot on the TLC plate other than that of the individual/ pure components represents
the presence of a degradation product, which can be eluted to identify/characterize the
degradant . Thus,TLC/HPTLC technique can be employed in the analysis of chemical
interactions between drug and excipients based on drug potency in the equilibrated samples.
.

25. ->High-Performance Liquid Chromatography
HPLC technique is a widely accepted and explored practice for compatibility studies including
several preformulation studies to quantitate the drug compound or identify and determine the
degree of incompatibilities .
Samples to be analyzed are diluted properly in an appropriate solvent and injected into the
HPLC system, thus the drug concentration can be determined from the standard calibration
curve of the known concentration drug within the expected range.
Having quantitatively analyzed the drug excipient samples subjected to isothermal stress testing
, where nateglinide and individual excipient’s mixtures were kept at high temperature for a
specified period (3-4 weeks), to expedite the interactive study.

26. 4 - Microscopical Technique
->Scanning Electron Microscopy
Surface morphology of the materials is determined by the use of this technique. This
technique is especially useful when distinguishing differences within the crystal structures
are available. But, this technique itself could not provide the chemical structure or the
thermal behavior of the analyzed component. As discussed earlier, SEM could be combined
with other techniques to have clear incompatibility activities. Thus, DSC, FT-IR, and
HSM are combined with SEM to characterize the interactions between drug and excipients
. For example, the melting peak of ibuproxam was modified due to an interaction between the
pharmaceutical excipient and the drug, consequently resulting in incompatibility .

27. 5 - Accelerated Stability Study
Extended mechanistic evaluation of physicochemical stability of the drug products is
determined by accelerated stability testing, where the degradation studies are accelerated
by placing the samples at different fixed temperature and humidity levels at varying time
durations. Thus shelf life or expiry information is the extrapolation of the long-term accelerated
outcome .
Mechanistic elucidation of degradation pathways are the basis of the stability of pharmaceutical
formulations. A recent study has demonstrated the compatibility of diazepam,
a benzodiazepine derivative antianxiety agent, with colloidal silicon dioxide, where confirmation
of accelerated stability study of 1:1 (w/w) mixtures was done with thermal analysis
(DSC and TGA) and spectroscopy (IR) .

28. 6 - Miscellaneous
->Radiolabeling technique
Radiolabeling (or isotopic labelling) is a technique used to track the passage of an isotope (an
atom with a detectable variation) through a reaction, metabolic pathway, or cell, called
radiolabeling technique. Atoms that have same atomic number, but have different masses are
known as isotopes. Some isotope of an atom have unstable nuclei which after nuclear reaction
emit characteristic radiation. These isotopes are called Radioisotopes, or more commonly
radionuclides.Nucleic acid may be modified with tags that enable detection or purification.
Resulting nucleic acid can be used to identify or recover other interesting molecules. Nucleic
acid can be labeled by isotopic and non- isotopic labeling methods.Isotopic labeling of nucleic
acids has been conducted by incorporating nucleotides containing radioisotopes. Which can be
detected specifically in solutions or much more commonly within a solid specimen.

29. ->Vapor phase osmometry
Vapor phase osmometry (VPO), also known as vapor-pressure osmometry, is an experimental
technique for the determination of a polymer's number average molecular weight, Mn. It works
by taking advantage of the decrease in vapor pressure that occurs when solutes are added to
pure solvent. This technique can be used for polymers with a molecular weight of up to 20,000
though accuracy is best for those below 10,000. Although membrane osmometry is also based
on the measurement of colligative properties, it has a lower bound of 25,000 for sample
molecular weight that can be measured owing to problems with membrane permeation.A typical
vapor phase osmometer consists of two thermistors, one with a polymer-solvent solution droplet
adhered to it and another with a pure solvent droplet adhered to it . A thermostatted chamber
with an interior saturated with solvent vapor . A liquid solvent vessel in the chamber; and an
electric circuit to measure the bridge output imbalance difference between the two thermistors.
The voltage difference is an accurate way of measuring the temperature difference between the
two thermistors, which is a consequence of solvent vapor condensing on the solution droplet
(the solution droplet has a lower vapor pressure than the solvent).

30. Kinetics of stability:-
Stability is defined as the capacity of a drugs substance to
remain within the established specification to maintain its
identity , strength , quality and purity till the date of
expiration .

31. Zero order kinetics
The zero order process can be defined as the one whose
rate is independent of the concentration of drug undergoing
reaction i.e. the rate of reaction cannot be increased further
by increasing the concentration of reactants.
𝑑𝐶
𝑑𝑡
= −𝐾0 C0
= - K0
Where K0 = zero-order rate constant .

32. C0
𝑑𝐶
𝑑𝑡
C
Time
slope = - K0
Graph of zero order reaction

33. Half - Life
Half life (t1/2 ) or half time is defined as the time period required for
the concentration of drug to decrease by one-half . When t = t 1/2 ,
C = C0/2
Equation -
𝐶0
2
= C0 - K0 t1 2
We get -
t1/2 =
𝐶0
2𝐾0
=
0.5 𝐶0
𝐾0
Equation shows that the t1/2 of a zero-order process is not constant
but proportional to the initial concentration of drug C0 and inversely
proportional to the zero - order rate constant K0 .

34. First order kinetics :-
First order process is the one whose rate is directly proportional to the
concentration of drug under-going reaction i.e. greater the concentration , faster
the reaction . It is because of such proportionality between rate of reaction and
the concentration of drug that a first - order process is said to follow linear
kinetics .
Equation :-
𝑑𝐶
𝑑𝑡
= - KC
When, n = 1 .
K = First - order rate constant .

35. Graph of first - order kinetics
𝑑𝐶
𝑑𝑡
C
Slope = - K

36. Stability Testing :-
Stability is defined as capability of a particular formulation in a
specific container/closure system to remain within its physical,
chemical, microbiological, toxicological, protective and informational
specifications. It is the extent to which a product retains, within the
specified limits, throughout its period of storage and use, the same
properties and characteristics possessed at the time of its
packaging.

37. SCOPE OF STABILITY TESTING:-
1-Provide evidence as to how the quality of drug product varies with
time.
2-Establish shelf life of drug product.
3-Determines recommended storage conditions.
4-Determine container closure system suitability.

38. IMPORTANCE OF STABILITY TESTING
1-Assurance to patient that drug is safe.
2-Legal requirement to provide data.
3-To protect the reputation of the manufacturer.
4-To provide a database.
5-To determine shelf life and storage conditions.
6-To verify that no changes have been introduced in the formulation.
7-Manufacturing process that can adversely affect the stability of the
product.

39. STABILITY TESTING METHODS:-
1. REAL TIME STABILITY TESTING
2. ACCELERATED STABILITY TESTING
3. RETAINED SAMPLE STABILITY TESTING
4. CYCLIC TEMPERATURE STRESS TESTING

40. Real time stability testing :-
• Real-time stability testing is normally performed for longer duration of the test
period in order to allow significant product degradation under recommended
storage conditions.
• The period of the test depends upon the stability of the product which should
be long enough to indicate clearly that no measurable degradation occurs and
must permit one to distinguish degradation from inter-assay variation.
• During the testing, data is collected at an appropriate frequency such that a
trend analysis is able to distinguish instability from day-to-day ambiguity.
• The reliability of data interpretation can be increased by including a single
batch of reference material for which stability characteristics have already been
established.

41. ACCELERATED STABILITY TESTING
•In accelerated stability testing, a product is stressed at several high (warmer
than ambient) temperatures and the amount of heat input required to cause
product failure is determined.
• This is done to subject the product to a condition that accelerates degradation.
•This information is then projected to predict shelf life or used to compare the
relative stability of alternative formulations.
•This usually provides an early indication of the product shelf life and thus
shortening the development schedule.
•In addition to temperature, stress conditions applied during accelerated stability
testing are moisture, light, agitation, gravity, pH and package.

42. • In accelerated stability testing the samples are subjected to stress,
refrigerated after stressing, and then assayed simultaneously.
• Because the duration of the analysis is short, the likelihood of instability in
the measurement system is reduced in comparison to the real-time stability
testing.
• Further, in accelerated stability testing, comparison of the unstressed product
with stressed material is made within the same assay and the stressed
sample recovery is expressed as percent of unstressed sample recovery.
• For statistical reasons, the treatment in accelerated stability projections is
recommended to be conducted at four different stress temperatures.

43. RETAINED SAMPLE STABILITY TESTING
1-This method is normally use for marketed product that require stability study .
2-In this study , stability sample , for retained storage for at least one batch a
year are selected .
3-If the numer of batches marketed exceeds 50 , stability samples from two
batches are recommended to be taken .
4-At the time of first introduction of the product in the market , the stability
samples of every batch may be taken , which may be decreased to only 2% to
5% of marketed batches at a later stage .
5-In this study , the stability samples are tested at predetermined intervals i.e. if
product has shelf life of 5 years ,it is conventional to test samples at
3,6,12,18,24,36,48 & 60 months .

44. CYCLIC TEMPERATURE STRESS TESTING
• This is not a routine testing method for marketed products. In this method, cyclic temperature
stress tests are designed on knowledge of the product so as to mimic likely conditions in
market place storage.
• The period of cycle mostly considered is 24 hours since the diurnal rhythm on earth is 24
hours, which the marketed pharmaceuticals are most likely to experience during storage.
• The minimum and maximum temperatures for the cyclic stress testing is recommended to be
selected on a product by- product basis and considering factors like recommended storage
temperatures for the product and specific chemical and physical degradation properties of the
products. It is also recommended that the test should normally have 20 cycles.

45. Zone I (TEMPERATE)United kingdom, Northern Europe, Russia, United states.
• Long term testing conditions- 210±20 C/45%RH
Zone II (SUBTROPICAL & MEDITERRANEAN)Japan, Southern Europe.
• Long term testing conditions- 250 C/60%RH
Zone III (HOT & DRY) • Iraq, India.
• Long term testing conditions- 300C/35%RH
Zone IV (HOT & HUMID) • Iran, Egypt.
• Long term testing conditions- 300C/65%RH CLIMATIC ZONES FOR
STABILITY

46. Thank You