The document discusses the critical importance of drug excipient compatibility in preformulation stages of dosage development, emphasizing various types of interactions and their effects on drug stability. It outlines the objectives of compatibility studies, methodologies for testing, and the impact of excipient properties on drug degradation mechanisms, including pH sensitivity and moisture absorption. Additionally, it provides examples of how specific excipients can destabilize certain drugs and highlights the role of statistical designs in evaluating compatibility in complex formulations.

1. By-Ayushi Patel

2.  Drug excipient compatibility represent an important
phase in the preformulation stage of the development of
all dosage forms.

3.  Excipient interaction :
 Different type of interaction : Physical,
Chemical & Physiological
 Excipient role in drug destabilization
 Excipient compatibility studies: Experimental
design.
 Excipient selection and criteria for parenterals.

4.  Before initiating drug product development, the formulation
scientists must fully consider the chemical structure of the
drug substance, the type of delivery system required and the
proposed manufacturing process.
 Initial selection of excipients should be based on appropriate
delivery characteristics , Potential mechanisms of degradation
for the drug in question should be considered. Known
chemical incompatibilities of common excipients may be
obtained from existing published information.

5. The objectives of drug–excipient compatibility studies is to
find out interactions between potential formulation excipients
and the API, thus allowing the rapid optimisation of a particular
dosage form with respect to patentability, processing, drug
release, elegance, and physical and chemical
stability.
In the typical drug–excipient compatibility testing program,
binary powder mixes are prepared by triturating API with the
individual excipients.
These powder samples, usually with or without added water
and occasionally compacted or prepared as slurries, are stored
under accelerated conditions
 Samples are analyzed by stability-indicating methodology,
for example- HPLC, CE and so forth

6.  Another approach is to conduct short-term stability
studies using prototype formulations, under stressed
conditions.
 Both the chemical stability, as measured by
chromatographic methods and physical stability as
measured by microscopic, particle analysis, in vitro
dissolution methods and so forth, are performed.

7.  A scientific approach, , is through a variety of statistical
designs.
 ‘One-factor-at-a-time’ methods have been supplanted by
factorial design. The factorial design can be useful for
screening purposes or as an aid to identifying effects in
complex systems.
 Excipients that should be included in these designs are fillers,
disintegrants, binders, lubricants and granulating liquids.

8.  However, it is well known that the chemical compatibility
of a drug substance in a binary mixture may differ
completely from a multi-component prototype formulation.
 Statistical designs can be used to determine the occurrence
of chemical interactions in complex formulations, with a
view towards establishing which excipients cause
incompatibility within a given mixture.

9. Excipients can be divided into four classes;
I. non-hygroscopic
II. slightly hygroscopic
III. moderately hygroscopic
IV. very hygroscopic
 In a closed system water from excipients will re-equilibrate
between the individual components of the formulation, via the
vapour phase, to attain the most thermodynamically stable
state.
 In practice, as most excipients contain more available
moisture than the drug substance, this results in the API being
the net recipient of the available moisture, resulting in an
increased potential for degradation.
.
Excipient role in drug destabilization

10.  The degradation rate for many drugs varies as a
function of pH of the surrounding environment. This
appears to be equally true in the solid state as it is in the
solution state.
 The pH within the micro-environment of a solid oral
dosage form can impact on the stability of the
formulation.

11.  In the case of hydrophobic excipients, there is the potential
for drug to be adsorbed onto the surface of the excipient,
resulting in the formation of a drug monolayer, which would
be more susceptible to chemical instability.
 Increased degradation of acetylsalicylic acid could be the
result of diffusion of the dissolved drug onto the
microcrystalline cellulose, in binary mixtures of the two
compounds.
 For maximum stability it is critical to optimise the pH of the
micro-environment, by judicious selection of excipients; this
is especially true for degradation pathways that are pH
sensitive.

12.  Study was done on compatibility of acetylsalicylic acid in
the presence of three common diluents: lactose,
microcrystalline cellulose and dicalcium phosphate.
 It was demonstrated that dicalcium phosphate, despite
having much lower moisture pick-up levels than
microcrystalline cellulose, had a greater destabilizing effect
on the drug. The authors attributed this to the alkalinity of
the dicalcium phosphate in the solid state.

13.  Levothyroxine tablets, 50 μg, continue to have numerous
product recalls due to degradation, Levoxythyroxine has a
complex stability profile and is sensitive to heat, light,
moisture, pH and oxidation. It was found that moisture and
the pH of the micro-environment influenced degradation the
most. They identified the best diluent for tablet manufacture
as being dibasic calcium phosphate, with a basic modifier
(sodium carbonate ,sodium bicarbonate or magnesium oxide)
 Degradation pathways observed were deiodination,
deamination and decarboxylation.

14. Table 2.4 Effect of modifiers on stability (percentage label claim) of
levothyroxine tablets, 50 μg,
40C/75% RH for 6 months
Months Without
modifier
Na2CO3 NaHCO3 MgO Tartaric
acid
Citric
acid
0 101.6 96.6 96.0 100.0 100.2 100.5
3 91.1 98.8 95.1 98.6 83.4 87.6
6 87.2 95.2 84.7 96.8 78.3 74.4

15.  Degradation pathway of pravastatin sodium was directly
linked to the micro-pH environment within the formulation.
Under neutral conditions (pH 6.5), the statin formed two
degradation products, a cyclic lactone and an internal
hydroxyl rearrangement product.
 However, as the pH was increased to 9.9 with the
incorporation of magnesium oxide into the blend, the only
degradation mechanism involved the formation of the
cleavage product, 2-methylpropanoic acid.

16.  Hydrolysis :One of the most common pathways of drug
product degradation is hydrolysis.
 The source of the raw materials can greatly influence
hydrolytic reactions. It could also influence the pH of
the micro-environment.

17.  Oxidation: Excipients play a key role in oxidation, either as a
primary source of oxidants, trace amounts of metals, or other
contaminants
Peroxides are a very common impurity in many excipients,
particularly polymeric excipients peroxide residues in
povidone (binder) and crospovidone (disintegrant) were
attributable to the formation of the N-oxide oxidation product
of raloxifene.

18.  Impact of processing on photostability:
Processing can impact on the photostability of drug products.
This is possibly due to the fact that photodegradation is a
surface-mediated phenomenon.
Though excipients within the formulation will reduce the
impact of photodegradation of API at the tablet surface
because of dilution effect.

19.  Dextrose is widely used as an isotonic media in parenteral
formulations. Sterilization using autoclaving has been
reported to induce the formation of fructose via an
isomerisation reaction, with the formation of 5-
hydroxymethylfurfural.
 Duloxetine hydrochloride, as an enteric-coated tablet was
destabilized by degradation products within these enteric
polymers succinyl and phthalyl residues from the
hydroxypropyl methylcellulose acetate succinate (HPMCAS)
and hydroxypropyl methylcellulose phthalate (HPMCP).
.

20.  Anti-oxidants
Ascorbic acid: Incompatible with acid- unstable drugs
Na bisulfite:+ Epinephrine Sulphonic acid dvt.
-Incompatible in Opthalmic solution containing Phenyl mercuric
acetate
Edetate salts: Incompatible with Zn Insulin, Thiomerosal,
Amphotericin & Hydralazine
 Preservatives
Phenolic Preservatives
-Lente- Insulin + Phenolic preservative Break-down of Bi-sulphide
Linkage in Insulin structure.
-Protamine- Insulin + Phenolic preservative tetragonal oblong crystals
which is responsible for prolong action of insulin.
20

21.  Surface active agents
Polysorbate 80:
 One must concern about the residual peroxide present in
Polysorbate.
 PS 80 Polyoxyethylene sorbitan ester of Oleic acid (Unsatd.F.A)
 PS 20 Polyoxyethylene sorbitan ester of lauric acid ( Satd.F.A)
 So PS 20 is less prone to oxidation than PS 80.
 Cosolvants
Sorbitol
 Increase the degradation rate of Penicillin in Neutral and Aqueous
solutions.
Glycerol
 Increase the mobility of freeze-dried formulation leading to peptide
deamidation.
21

22. 22
Sr
.
N
o.
DRUG EXCIPIENT
INTERACTION
OBSERVED
1.
Nicotinamide &
dimethylisosorbide
Propylene-glycol Hemolysis (in vivo effect)
2.
Paclitaxel,
Diazepam,
Propaniddid and
Alfaxalone
Cremophor EL
(polyoxyl 35
castor oil)
Precipitation of Cremophor EL
COSOLVENTS
Sr.
No.
DRUG EXCIPIENT INTERACTION
1. Lidocaine Unpurified
sesame oil
Degradation of
lodocaine
2.
Calcium chloride,
phenytion sodium,
tetracycline
hydrochloride
Soybean oil Incompatible with
All.
OILSANDLIPIDS

23. 23
DRUG EXCIPIENT
INTERACTION
OBSERVED
Proteins Tween 80 and
other
nonionic
polyether
surfactants
Surfactants undergo oxidation and the
resultant alkyl hydroperoxides
formed contribute to the
degradation of protein.
Protein
formulations
Thiols such as
cystiene,
glutawthion
e asnd
thioglycerol
Most effective in stabilizing protein
formulations containing peroxide-
forming surfactants.
SURFACTANTS & CHELATING AGENTS
Dexamathasone,
Estradiol,
Iterleukin-2 &
Proteins and
Peptides
Modified
cyclodextrins,
Solubilize and stabilize drugs without
apparent compatibility problems.

24. 24
DRUG EXCIPIENT INTERACTION
N-nitrosourea Tris buffer Form stable complex with N-nitrosourea
and retard the degradation of this agent.
5-flurouracil Tris buffer Tris buffer will degrade 5-flurouracil,
causing the formation of two degradation
products that can cause serious
cardiotoxicities
Chlorpromazine Meta-cresol Incompatible
Recombinant human
interferon gamma
Benzyl alcohol Benzyl alcohol caused the aggregation of
the protein
Cisplatin Sodium
metabisulfite
Sodium metabisulfite inactivates cisplatin
BUFFERS,ANTIMICROBIALS & ANTIOXIDENTS