Drug excipient compatibility
- 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