Biomedical subjects

Saranjit Singh

Publications and source records attributed to Saranjit Singh.

25 records · Page 2Linked to original sources

PubMed2003

The ICH guidance in practice: stress decomposition studies on three piperazinyl quinazoline adrenergic receptor-blocking agents and comparison of their degradation behaviour.

Stress degradation studies were carried out on three piperazinyl quinazoline alpha(1)-adrenergic receptor blockers, viz. prazosin, terazosin, and doxazosin, following the conditions prescribed in the parent drug stability testing guideline (Q1AR) issued by International Conference on Harmonization (ICH). All drugs showed significant decomposition at 80 degrees C in acidic conditions (0.1 M HCl) and complete degradation in alkaline conditions (0.1 M NaOH). Under both these conditions, 2-piperazinyl-6,7-dimethoxy-4-aminoquinazoline was formed as a major decomposition product in all three drugs. The degradation pattern under ICH-prescribed photolytic conditions in liquid and solid states was also similar for all the drugs. The light exposure resulted in the formation of a cluster of degradation products. No degradation was observed in neutral and oxidative conditions. In solid state, all drugs were stable at 50 degrees C in a 1-month study. In alkaline conditions, the order of sensitivity to degradation of the three drugs was doxazosin>terazosin>prazosin, while the same was terazosin>doxazosin>prazosin under acidic conditions. Mechanistic explanation is provided for the variable behaviour of decomposition.

Acids↗

PubMed2003

Evaluation of the recently reported USP gradient HPLC method for analysis of anti-tuberculosis drugs for its ability to resolve degradation products of rifampicin.

The recently notified USP gradient HPLC method for quantitative determination of rifampicin, isoniazid and pyrazinamide in fixed dose combination (FDC) formulations was evaluated to determine its ability to resolve major degradation products of rifampicin, viz. 3-formylrifamycin SV, rifampicin N-oxide, 25-desacetyl rifampicin, rifampicin quinone, and the newly reported isonicotinyl hydrazone, an interaction product of 3-formylrifamycin and isoniazid. The first observation was that the requirements of theoretical plates listed in the given method were met for rifampicin, but not for isoniazid and pyrazinamide, even on columns of different makes. The resolving power of the method was also dependent upon make of the column. On two of the three columns of the three tested, it was able to resolve most degradation products, except rifampicin N-oxide and 25-desacetylrifampicin, which were overlapping. The method was modified and an overall satisfactory resolution for all components was obtained by changing the buffer: organic modifier ratio of solution B in the gradient from 45:55 to 55:45 and decreasing the flow rate from 1.5 to 1.0 ml/min, keeping all other conditions constant.

Antibiotics, Antitubercular↗

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↗

PubMed2002

Behavior of uptake of moisture by drugs and excipients under accelerated conditions of temperature and humidity in the absence and the presence of light. 1. Pure anti-tuberculosis drugs and their combinations.

An investigation was carried out to determine the behavior of moisture gain by four anti-tuberculosis drugs, viz. rifampicin, isoniazid, pyrazinamide and ethambutol, when exposed in pure form and in combinations to accelerated conditions of 40 degrees C and 75% RH, in the absence and the presence of light. Weight gain was seen only in those samples that contained ethambutol, and this behavior was observed both in dark and lighted chambers. There was a decrease in moisture uptake with an increase in the number of drugs in the mixture. Another observation was a higher weight gain by the mixture of ethambutol and isoniazid in a dark chamber, than either pure ethambutol or drug combinations containing ethambutol. The most interesting finding was an overall acceleration of weight gain in the presence of light as compared with dark conditions, which is a hitherto unknown phenomenon.

Adsorption↗

PubMed2002

Development of validated stability-indicating assay methods--critical review.

This write-up provides a review on the development of validated stability-indicating assay methods (SIAMs) for drug substances and products. The shortcomings of reported methods with respect to regulatory requirements are highlighted. A systematic approach for the development of stability-indicating methods is discussed. Critical issues related to development of SIAMs, such as separation of all degradation products, establishment of mass balance, stress testing of formulations, development of SIAMs for combination products, etc. are also addressed. The applicability of pharmacopoeial methods for the analysis of stability samples is discussed. The requirements of SIAMs for stability study of biotechnological substances and products are also touched upon.

Chemistry, Pharmaceutical↗

PubMed2002

New findings on degradation of famotidine under basic conditions: identification of a hitherto unknown degradation product and the condition for obtaining the propionamide intermediate in pure form.

The degradation behavior of famotidine (1) was investigated in 25% ammonia solution and in 2 M NaOH. The hydrolysis of the drug in ammonia resulted in separation of [3-[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]propionamide (3), an impurity listed in British Pharmacopoeia. The treatment with 2 M NaOH resulted in formation of [3-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]propionyl]sulfamide (2) and 3. These products further decomposed to [3-[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]propionic acid (4) and a heretofore unknown product, 5. The latter separated out in the reaction mixture as brown shiny crystals. Proton and carbon-13 nuclear magnetic resonance spectroscopy, mass spectrometry, and elemental analysis of the charcoal-treated product established the structure. The formation of 5 is postulated to involve abstraction of a proton from the alpha-carbon of intermediates 2 and 3 followed by elimination of the thiol moiety.

Amides↗

PubMedDate not supplied

Evidence of efflux-mediated and saturable absorption of rifampicin in rat intestine using the ligated loop and everted gut sac techniques.

This study was carried out to explore whether efflux-mediated and saturable mechanisms play any role toward poor and variable intestinal absorption of rifampicin. In situ segmental permeability of rifampicin at various residence times was determined in rat gastrointestinal tract using the ligated loop technique. The involvement of efflux-mediated and saturable absorption of rifampicin was studied in rat intestine using the everted sac method. The samples were analyzed by a validated HPLC method. Rifampicin showed decreased permeability in jejunum and ileum with an increase in residence time. The permeation of rifampicin from the serosal to the mucosal side (secretion) was significantly higher than permeation from the mucosal to the serosal side (absorption) of jejunum and ileum. This indicated the involvement of efflux-mediated transport. Addition of verapamil, an inhibitor for P-glycoprotein (Pgp), multidrug resistance associated protein-2 (MRP-2), and other related transporters, increased absorption of rifampicin in jejunum and ileum by 2-3-fold and decreased secretion by almost 4-fold. The permeation rate (flux) of rifampicin through duodenum increased with concentration up to 300 microg/mL, becoming constant thereafter, indicating the existence of saturable absorption. There was no saturable permeation in jejunum and ileum. Thus the present study indicates the involvement of efflux-mediated and saturable absorption mechanisms of rifampicin in rat intestine, which act as barriers to the absorption of the drug. This explains the drug's poor absolute bioavailability. As Pgp varies from person to person to an extent of 2-8-fold, it can be one direct reason for the interindividual variable bioavailability shown by rifampicin.

Animals↗