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At least 163 records · Page 9Linked to original sources
PubMed2003

Behavior of decomposition of rifampicin in the presence of isoniazid in the pH range 1-3.

The extent of decomposition of rifampicin in the presence of isoniazid was determined in the pH range 1-3 at 37 degrees C in 50 min, the mean stomach residence time. With increase in pH, the degradation initially increased from pH 1 to 2 and then decreased, resulting in a bell-shaped pH-decomposition profile. This showed that rifampicin degraded in the presence of isoniazid to a higher extent at pH 2, the maximum pH in the fasting condition, under which antituberculosis fixed-dose combination (FDC) products are administered. At this pH and in 50 min, rifampicin decomposed by approximately 34%, while the fall of isoniazid was 10%. The extent of decomposition for the two drugs was also determined in marketed formulations, and the values ranged between 13-35% and 4-11%, respectively. The extents of decomposition at stomach residence times of 15 min and 3 h were 11.94% and 62.57%, respectively, for rifampicin and 4.78% and 11.12%, respectively, for isoniazid. The results show that quite an extensive loss of rifampicin and isoniazid can occur as a result of interaction between them in fasting pH conditions. This emphasizes that antituberculosis FDC formulations, which contain both drugs, should be designed in a manner that the interaction of the two drugs is prevented when the formulations are administered on an empty stomach.

Capsules↗
PubMed2004

Stabilization of rasburicase and physico-chemical characterization of the resulting injectable formulation.

Rasburicase (Fasturtec/Elitek) is a new generation of recombinant urate oxidase administred therapeutically by intravenous infusion for the prevention or treatment of hyperuricemia during chemotherapy. To ensure a long storage period, a freeze-dried formulation was developed to guarantee the molecular integrity and enzyme activity. Screening of potential excipients was the first stage of the preformulation study. The selection was based on stability results (rasburicase solution with excipient) obtained with the isoelectric focusing profiles and residual enzyme activity. The different excipients were classified as stabilising, neutral or destabilising. A stability study was then carried out on different freeze-dried formulations containing the usual bulking agents for freeze-drying, excipients with a high glass transition temperature or competitive enzyme inhibitors having a stabilising effect. A mannitol/alanine mixture in phosphate buffer was selected from these preliminary results. Finally, the optimal content of mannitol and alanine in the freeze-dried powder was determined by an experimental design study. The water content and the appearance of the "cake", the osmolality, pH, clarity, and enzyme activity of the reconstituted solution were assessed. The formula with a mannitol/alanine ratio of 0.7 was found to be the best composition. Differential scanning calorimetry and ThermoStimulated Current technique experiments were carried out to study the amorphous phase. A glass transition temperature of about 45-500 degrees C was found. Glassy state is known to preserve stability, which was verified by the real stability data. X-ray diffraction studies have shown that alanine is in a crystallised state and that mannitol remains amorphous. Crystallised excipients participate in forming the structure of the powder and therefore help to prevent any collapse. Amorphous mannitol creates a surrounding medium favourable to the stability of the protein.

Alanine↗
PubMed2003

A new approach to accelerated drug-excipient compatibility testing.

The purpose of this study was to develop a method of qualitatively predicting the most likely degradants in a formulation or probing specific drug-excipient interactions in a significantly shorter time frame than the typical 1 month storage testing. In the example studied, accelerated storage testing of a solid dosage form at 50 degrees C, the drug substance SB-243213-A degraded via the formation of two oxidative impurities. These impurities reached a level of 1% PAR after 3 months. Various stressing methods were examined to try to recreate this degradation and in doing so provide a practical and reliable method capable of predicting drug-excipient interactions. The technique developed was able to mimic the 1-month's accelerated degradation in just 1 hr. The method was suitable for automated analysis, capable of multisample stressing, and ideal for use in drug-excipient compatibility screening.

Chemistry, Pharmaceutical↗
PubMed2005

Formation of oligonucleotide adducts in pharmaceutical formulations.

During preformulation studies, we observed that oligonucleotide extracted from topical formulations contained considerable amounts of covalently modified oligonucleotide adducts. In this report, we describe the identification and characterization of reaction products that form when PS-oligodeoxyribonucleotide ISIS 2302 (1) is brought into contact with aqueous solutions of glycerol-derived excipients. Compatibility tests showed that the presence of certain glycerides in the formulation lead to adduct formation (1+58x amu, 1+72x amu, 1+58x+72y amu, x, and y are the number of modifications on one oligonucleotide strand). No adduct formation was observed in the presence of triglycerides or propylene glycol-derived excipients used in the study. Using nucleosides as model compounds, two modifications of deoxyguanosine were isolated by preparative reversed phase (RP)-high pressure liquid chromatography (HPLC) and characterized by nuclear magnetic resonance (NMR) and HPLC-mass spectrometry (MS). Modifications were identified as N2-(1-carboxymethyl)- and N2-(1-carboxyethyl) derivatives of 2'-deoxyguanosine. The mechanism of formation of these adducts may involve advanced glycation reactions possibly caused by excipient impurities or degradation products such as glyceraldehyde or glyceraldehyde derivatives.

Chemistry, Pharmaceutical↗
PubMed1995

Compatibility and stability of aztreonam and vancomycin hydrochloride.

The physical compatibility and chemical stability of aztreonam and vancomycin hydrochloride when combined at clinically used high and low concentrations were studied. Admixtures consisting of aztreonam 4 mg/mL and vancomycin 1 mg/mL (as the hydrochloride salt) in 5% dextrose injection, aztreonam 4 mg/mL and vancomycin 1 mg/mL in 0.9% sodium chloride injection, aztreonam 40 mg/mL and vancomycin 10 mg/mL in 5% dextrose injection, and aztreonam 40 mg/mL and vancomycin 10 mg/mL in 0.9% sodium chloride injection were prepared in triplicate in polyvinyl chloride containers. Three containers of each type of admixture were stored at 4, 23, and 32 degrees C. Samples were removed immediately and at various time points over 31 days. Compatibility was assessed by visual examination, with a turbidimeter, and with a particle sizer-counter. Stability was determined by stability-indicating high-performance liquid chromatography (HPLC). All the admixtures initially appeared clear to the unaided eye after the disappearance of a transient white swirl in the high-concentration admixtures (aztreonam 40 mg/mL and vancomycin 10 mg/mL). However, the high-concentration admixtures immediately developed unacceptable levels of a microcrystalline precipitate when viewed with a high-intensity fiber-optic light source. Easily visible gross turbidity and precipitation formed after various periods but often within 24 hours. HPLC showed aztreonam 4 mg/mL and vancomycin 1 mg/mL in 5% dextrose injection to be a stable combination for 7 days at 32 degrees C, 14 days at 23 degrees C, and 31 days at 4 degrees C. In 0.9% sodium chloride injection, the drugs in the low-concentration admixtures were stable for 7 days at 32 degrees C and for 31 days at 4 and 23 degrees C. Stability of the combination in the high-concentration admixtures was maintained for 3 days at 23 and 32 degrees C and for 14 days at 4 degrees C. Aztreonam and vancomycin hydrochloride were considerably less compatible and stable in the high-concentration admixtures than in the low-concentration ones.

Anti-Bacterial Agents↗
PubMed1996

Stability of acetazolamide, allopurinol, azathioprine, clonazepam, and flucytosine in extemporaneously compounded oral liquids.

The stability of drugs commonly prescribed for use in oral liquid dosage forms but not commercially available as such was studied. Acetazolamide 25 mg/mL, allopurinol 20 mg/mL, azathioprine 50 mg/mL, clonazepam 0.1 mg/mL, and flucytosine 10 mg/mL were prepared in 1:1 mixture of Ora-Sweet and Ora-Plus (Paddock Laboratories), a 1:1 mixture of Ora-Sweet SF and Ora-Plus (Paddock Laboratories), and cherry syrup and placed in polyethylene terephthalate bottles. The sources of the drugs were capsules and tablets. Six bottles were prepared per liquid; three were stored at 5 degrees C and three at 25 degrees C, all in the dark. A sample was removed from each bottle initially and at intervals up to 60 days and analyzed for drug concentration by stability-indicating high-performance liquid chromatography. At least 94% of the initial drug concentration was retained in all the oral liquids for up to 60 days. There were no substantial changes in the appearance or odor of the liquids, or in the pH. Acetazolamide 25 mg/mL, allopurinol 20 mg/mL, azathioprine 50 mg/mL, clonazepam 0.1 mg/mL, and flucytosine 10 mg/mL were stable for up to 60 days at 5 and 25 degrees C in three extemporaneously compounded oral liquids.

Acetazolamide↗