Drug excipient compatibility
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Transcript of Drug excipient compatibility
Drug- Excipient Compatibility
By-Ayushi Patel
Drug excipient compatibility represent an important phase in the preformulation stage of the development of all dosage forms.
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.
Drug- Excipient Compatibility Experimental Design
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.
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 chemicalstability.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
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.
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.
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.
Excipients can be divided into four classes;I. non-hygroscopicII. slightly hygroscopicIII. moderately hygroscopicIV. 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.
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Excipient role in drug destabilization
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.
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.
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.
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.
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
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.
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.
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.
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.
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).
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DRUG EXCIPIENT COMPATIBILTY IN PARENTERAL PRODUCTS
Anti-oxidants Ascorbic acid: Incompatible with acid- unstable drugsNa 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.
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Surface active agentsPolysorbate 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.
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Sr.No.
DRUG EXCIPIENT INTERACTIONOBSERVED
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 withAll.
OILS
AND
LIP
IDS
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DRUG EXCIPIENT INTERACTIONOBSERVED
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,
glutawthione 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.
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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
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