Formulation development for vaccines poses additional challenges as the vaccine antigen can be of different types, including live attenuated viruses, inactivated viruses, purified recombinant proteins, purified viral proteins, viruslike particles, inactivated bacterial toxins and polysaccharides. Hplc analysis of cresols and phenol on astec cyclobond i. Phenolic excipients of insulin formulations induce cell. Prior to world war ii, multimillion pound quantities of cresols were produced annually in the united states, and domestic production and sales of cresols have steadily increased over the past several decades. Hplc analysis of cresols and phenol on astec cyclobond i 2000. Drytarry, medicinalleathery odor, conventionally described as phenolic. One source has rated pchloromcresol as very toxic, with a probable lethal dose to humans of 50 to 500 mgkg. Useful as a floralizing companion to indole in sharpexotic flower fragrances.
Cresolcresylic acid ocresol cresolcresylic acidmcresol p. Mcresol is a colorless liquid with a sweet tarry odor. Final report on the safety assessment of sodium p chloro. Us patent application for pharmaceutical formulation. In its chemical structure, a molecule of cresol has a methyl group substituted onto the ring of phenol. For another set of samples, mcresol was added first in the peptide solution followed. Commonly screened preservatives include m cresol, benzyl alcohol or phenol, phenoxyethanol and chlorobutanol. National toxicology information program, national library of medicine, bethesda, md. In addition, l929 cells were incubated with either pure phenol or mcresol in a dose dependent manner 02. Optimization of preservatives in a topical formulation using experimental design article in international journal of cosmetic science 316. Insulin degludec was prepared as described earlier. It is a derivative of phenol and is an isomer of o cresol and m cresol.
We never went over this reaction in class so i have no. While pchlorom cresol is approved for preservative use b. Handbook of toxic and hazardous chemicals and carcinogens. Packaging 1 kg in glass bottle 10, 25 kg in composite drum other notes download our flavors and fragrances catalog to view our entire product line. Both of these substances are very toxic, and for someone who is injecting 20 units of insulin per day, means also 300 ppm of phenol per day and 344 ppm of m cresol. Phenolic excipients of insulin formulations induce cell death. These processes will likely lead to the clinical signs of skin irritation. Because the zinc ions are commonly considered in insulin. It achieves the desired meta orientation of the final substituents by introducing a metadirecting substituent the aldehyde group earlyon in the synthetic. Cresolcresylic acid a ocresol mcresol pcresol 19773, 95487, 108394, 106445. Streams n and 24 recombine and enter the ocresolxylenol separation column oci. Cresol c7h8o, any of the three methylphenols with the same molecular formula but having different structures.
How can metacresol be made, given that the hydroxyl group is. He also offered some observations on the choice of antimicrobial preservatives that are used in formulations in europe. Cresolcresylic acid cresolcresylic acid a ocresol mcresol pcresol 19773, 95487, 108394, 106445 hazard summary ambient air contains low levels of cresols from automobile exhaust, power plants, and oil refineries. The term phenolic preservative as used herein, typically refers to art accepted phenolic preservatives such as chlorocresol, mcresol, phenol, or mixtures thereof.
The chosen idlh is based on the isomer with the highest vapor pressure, that of ocresol, which yields a saturated concentration of 323 ppm at 25 c. Screening of various preservatives either alone or in combination is recommended prior to selection 18. M cresol is a colorless liquid with a sweet tarry odor. One source has rated pchloro m cresol as very toxic, with a probable lethal dose to humans of 50 to 500 mgkg. Pharmaceutical biotechnology effect of antimicrobial.
Investigation of the physicochemical properties that. The national toxicology program ntp of the national institutes of. It is a colourless, viscous liquid that is used as an intermediate in. Packaging 1, 5, 10 g in glass bottle biochemphysiol actions m cresol purple is a ph indicator. It is also one of the key contributors to the beefy flavor in bovine meat. This indicated that the compounds causing cytotoxicity of insulin formulations are phenol and m cresol. Mechanisms of mcresolinduced protein aggregation studied using a model protein cytochrome c surinder m. Pathways for the degradation of mcresol and pcresol by. Pathways for the degradation of m cresol and p cresol by pseudomonas putida. The chromatographic method described here was found to be reliable for quantifying m cresol in pth formulation. Final report on the safety assessment of pchloromcresol. In the cymene cresol process, toluene is alkylated with propylene to give isomers of cymene, which can be oxidatively dealkylated analogous to the cumene process.
Synthesis of cresols and xylenols from benzene and methanol. Excipient selection in biologics and vaccines formulation. We never went over this reaction in class so i have no idea how to do it please help someone. View export data from india, price, monthly trends, major countries, major ports for cresol, ortho finished dosage formulations. Us30383a purification of mcresol from mixtures of m. Mechanisms of mcresolinduced protein aggregation studied using a model protein cytochrome c. Formulations were made by dissolution of insulin degludec followed by addition of 1. Instability of protein in aqueous solution condition for a multidose formulation may force lyophilisation without the preservative. It is derived from phenol and is commonly extracted from coal tar. It is a partially lipophilic moiety which strongly binds to plasma protein close to 100% under normal conditions.
How can metacresol be made, given that the hydroxyl group. This chemical can react vigorously with strong oxidizers and strong bases. Antimicrobial preservatives in protein drugs pharmaceutical. Packaging 1 kg in glass bottle 10, 25 kg in composite drum other. Mechanisms of mcresolinduced protein aggregation studied. National toxicology program chemical repository database. Structure and pharmaceutical formulation development of a. Us patent for stabilized insulin formulations patent.
A highly sensitive method for the quantitation of polysorbate. While benzyl alcohol is the preferred antimicrobial preservative in europe, concentrations of 0. These forms occur separately or as a mixture, which can also be called cresol or more specifically, tricresol. High purity products supplied by spectrum are indicative of a grade. Taking all this into consideration, m cresol is likely a stabilizer but zinc is likely a destabilizer for compound 100 and the other incretininsulin conjugates disclosed herein. It plays a role in how your page is seen by search engine crawlers, and how it appears in serps. Mallela1,2 1department of pharmaceutical sciences and center for pharmaceutical biotechnology, school of pharmacy, university of colorado denver. Cresol is a medicine available in a number of countries worldwide. Prior to world war ii, multimillion pound quantities of cresols were produced annually in the united states, and domestic. These two compounds have similar mass spectra to o.
Release to the environment of this substance can occur from industrial use. Here is a synthesis of mcresol starting from benzene. Feed consumption was depressed during the first study week in all highdose groups of animals and weight. M cresol, phenol, and benzyl alcohol are the most widely used antimicrobial agents used in protein multidose products. They are generally used as single agents, although insulinprotamine suspension products, for example, contain both m cresol and phenol. This material is provided for educational purposes only. While benzyl alcohol is the preferred antimicrobial preservative in. Mcresol is a cresol with the methyl substituent at position 3. A comparison of the oxidation rates of various compounds by whole cells of pseudomonas putida 3, 5 indicated that m cresol is metabolized by oxidation to 3hydroxybenzoate followed by hydroxylation to ge. Optimization of preservatives in a topical formulation. Another method, involves carbonylation of a mixture of methallyl chloride and acetylene in the presence of nickel carbonyl. It reacts violently with nitric acid, oleum, chlorosulfonic acid.
Niosh pocket guide to chemical hazards mcresol cdc. M cresol is a cresol with the methyl substituent at position 3. The addition of mcresol promotes even further the selfassociation but final zinc addition to prepare the pharmaceutical formulation has no effect. Handbook of toxic and hazardous chemicals and carcinogens, 1985. Specificity of the method for m cresol in the presence of pth, and excipients such as mannitol, sodium acetate, and glacial acetic acid was studied in terms of resolution of peaks observed and peak area of m cresol. Metacresol mcresol is used as bactericide in the biotechnological processing of pharmaceuticals.
In shortterm studies in rats and mice, an o cresol, m cresol, p cresol or m cresol p cresol mixture at 30,000 ppm in the diet produced increases in liver and kidney weights, deficits in liver. It plays a role in how your page is seen by search engine. Patty 1963 reported that rats exposed for 8 hours to a saturated concentration of cresol vapors survived the exposure smyth 1956. Final report on the safety assessment of pchloromcresol pchloromcresol is a substituted phenol that functions as a cosmetic biocide preservative in skin care and suntan cosmetic formulations. Metacresol mcresol, usp,ep msds quality excipients. Data were available to demonstrate that mcresol and ocresol when tested at 0. Shi s, chen z, rizzo jm, semple a, mittal s, et al. Validation studies showed that the developed hplc method was selective, linear, precise, and accurate. Eye contact in the case of contact with eyes, rinse immediately with plenty of water and seek medical advice. As shown here, even short exposure of phenol m cresol induces cell death which further stimulates inflammatory and repair processes at the infusion site.
I was wondering if anyone here was thinking about toxic substances present in insulin formulations. Cresol, ortho finished formulations export data price. A meta description is an html tag in the html code of your website, which allows you to customize a section of text that describes the page itself. Cdc niosh pocket guide to chemical hazards mcresol. Validation of a simple rphplc method developed for the. One should not drive a vehicle if using the medicine makes you drowsy, dizzy or lowers your bloodpressure extensively.
Pharmaceutical biotechnology effect of antimicrobial preservatives on partial protein unfolding and aggregation regina l. In addition, l929 cells were incubated with either pure phenol or m cresol in a dose dependent manner 02. Time min mobile phase a % mobile phase b % comment. Find the product when mcresol reacts with sodium hydroxide. If you experience drowsiness, dizziness, hypotension or a headache as sideeffects when using m cresol medicine then it may not be safe to drive a vehicle or operate heavy machinery. Release to the environment of this substance can occur from. It may be that sodium pchloromcresol, pchloromcresol. To verify this, pth, formulation buffer, mobile phase, and m cresol standard were.
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