Stability study of sulfamethoxazole and trimethoprim tablets available in Thailand.

From 5 brands (4 locally manufactured and 1 innovator) of 400/80 mg Sulfamethoxazole and Trimethoprim tablets, 3 conformed to pharmacopoeial specification and packed in different types of bottles (glass, plastic), all uncoated tablets, were selected for accelerated stability studies. It was found that color of tablets changed inversely proportional to temperature, humidity and high temperature evidently had no influence on the trimethoprim stability, but had influence on sulfamethoxazole and excipient at high temperature (>50oC, 70% R.H.). By calculation, rates of the increase of sulfanilamide and sulfanilic acid, mostly appeared to be a first-order reaction. The increasing rate constants at a relative humidity of 75% for each brand were correlated with the temperatures according to the Arrhenius equation at 40, 50 and 60oC. The activation energies of tablets out and in containers were in the ranges of 9-21 and 18-28 Kcal/mole respectively. Degradation at 70oC, 75% R.H., was not used in calculation because of its deviation from Arrhenius plot. By comparison from accelerated 60oC, it was found that degradation rate constants of tablets in containers tended to be significantly lower than those out containers. The rates for the locally made tablets in containers were higher than those of the innovator. By calculation using USP standard, the shelf lives of tablets of all brands were found to be larger than 5 years, which were agree with those obtained by storing at ambient temperature. The tablets were found to retain their compliance with the pharmacopoeial standard by storing at ambient temperature after 15 months, but the real shelf life could not be stated yet. The authors suggest that in manufacturing of solid dosage forms, especially tablets and capsules, follow-up stability study must be conducted with concentration on dissolution determination.

Quality problem of drug products produced in hospitals in Thailand.

Problems of drug quality prepared in hospitals in Thailand were collected during January 1990-December 1998. From laboratory findings, evidence of instability in 649 samples were evaluated. Problems were found in various types of pharmaceutical dosage forms (oral liquid preparation 43.8%, parenteral products 21.6%, topical preparation 20.6%) and water samples for pharmaceutical purposes 14.0%. The types of instability were: chemical change 44.8%, microbiological change 25.3%, physical change 17.5% ( appearances 3.8 per cent and properties 13.7 per cent) and a combination of changes 12.4%. In addition, expiration dates were not stated on the labels (94.3 per cent) since these products may be dispensed a short time after preparations, instability was found between 1 month and over 12 months after manufacturing with the highest frequency of occurrence filling within 2-3 months. For the products with a stated shelf-life of 6 months, 1 or 2 years, stability problems of 37 samples occurred between 1 month to 6 months after manufacturing, with maximum occurance at 1 month. Type of containers used were problematic. It was found that 64.5 per cent of problems occurred in transparent glass bottles and 36.7 per cent in semi-transparent plastic bottle packages. To avoid quality problems, the authors suggest that hospitals must be developed and use high-quality active ingredients, water, production process and areas which comply with current Good Manufacturing Practices requirement.

Stability problems of non-essential drugs used in hospitals in Thailand.

A study of stability problems of non-essential drugs purchased by 658 hospitals in Thailand has been carried out since 1993. During 1990-1997, selective sampling of 316 cases related to stability problems of non-essential drugs was undertaken through questionnaires sent to 658 government hospitals and from laboratory findings. The stability problems were identified and categorised into pharmacopoeial non-compliance (56.3 per cent) and physical appearances (43.7 per cent). Most problems (81.0 per cent) occur in locally-made drug products. In addition, 87.3 per cent of drugs were found to have no expiration dates stated on the labels and instability was found between 1-3 months and over 7 years after manufacturing, with the highest frequency of occurrence falling within 10-12 months (25.6 per cent). For products with a stated shelf-life, stability problems in 29 samples occurred in 5 to 100 per cent of shelf-life period, with 11 expired samples being reported. The problem was mainly found in drugs in tablet form (58.9 per cent), followed by injectable drugs (18.0 per cent) and oral liquid preparations (11.7 per cent). The problem was largely found in drugs which had transparent glass bottle packages (22.8 per cent) and semi-transparent plastic bottle packages (24.1 per cent). Factors affecting the stability of drug products have already been stated in many textbooks on stability; however, some drug substances have not been mentioned in any book. Therefore, to avoid stability problems, proper formulations must be developed using standard quality raw materials and packaging under Good Manufacturing Practices requirements. The authors suggest that manufacturers should use high-quality active ingredients, suitable formulations and packaging which comply with current Good Manufacturing Practices, in order to prevent stabilty problems occurring in drug products. In addition, proper storage conditions in accordance with the labelling should be strictly practiced in hospitals.

Survey on stability of pharmaceutical products in national list of essential drugs used in hospitals in Thailand.

A survey on stability problems of essential drugs purchased by 989 hospitals and provincial public health offices in Thailand has been carried out since 1993. During 1990-1997, selective sampling of 1799 cases related to stability problems of 206 drug substances was undertaken through questionnaires sent to 658 government hospitals and from laboratory findings. The stability problems were identified and categorised into pharmacopoeial non-compliance (25.2 per cent) and physical appearances (74.8 per cent). Most problems (91.7 per cent) occur in locally-made drug products. In addition, 84.2 per cent of drugs were found to have no expiration dates stated on the labels and instability was found between < 15 days and over 11 years after manufacturing, with the highest frequency of occurrences falling within 10-12 months (45.6 per cent). For products with a stated shelf-life (15.8 per cent), stability problems occurred from within 2 months after manufacturing to over 5 years; with maximum occurence at 61-70 per cent of shelf-life. Factors affecting the stability of drug products have already been stated in many textbooks on stability. Therefore, to avoid stability problems, proper formulations must be developed using standard quality raw material and packaging under Good Manufacturing Practices requirements. The means of drug transportation to hospitals, drug distribution chains and storage conditions in hospitals have also been considered as factors creating stability problems. The authors suggest that manufacturers should use high-quality active ingredients, suitable formulations and packaging which comply with current Good Manufacturing Practices, in order to prevent stabilty problems occurring in drug products. Proper storage conditions in accordance with the labelling should be strictly practiced in hospitals. Moreover, stability study on transportation factor should be included in stability study protocol for at least 30 days.

Colour stability of tetracycline hydrochloride capsules.

In a preliminary study of various excipients that could stabilize the colour of tetracycline hydrochloride (TC), it was found that sodium metabisulfite yielded the maximum stability and it was then chosen for a further study. Comparative studies of the colour and chemical stability of TC powder in capsules in different of colour capsule shells, different types of containers, as well as the omission and addition of 0.1% sodium metabisulfite were then made. The results showed that, after 36 months at ambient temperature, there was no significant difference in colour of the drug powder in each formula resulting from the type of container or colour of the capsule shell. At ambient temperature, the addition of sodium metabisulfite prolonged shelf life from 3 to 9 mnths in colour stability aspect, but the rate constant of 4-epianhydrotetracycline production (Zero order reaction) increased from 0.0012-0.0056% to 0.0052-0.0093% per month. The tentative shelf life of TC with and without sodium metabisulfite at 95% confidence were then more than 5 years. However, storage in refrigerator (14-15oC) for 36 months, TC preparation with and without sodium metabisulfite gave good colour stability (yellow powder) and a shelf life longer than 36 months.