|Year : 2019 | Volume
| Issue : 2 | Page : 152-154
An unusual color change in tetracycline HCl powder – from drug to poison
Department of Biochemistry, Faculty of Natural Sciences, Chukwuemeka Odumegwu Ojukwu University, Anambra State, Nigeria
|Date of Web Publication||25-Mar-2019|
Department of Biochemistry, Faculty of Natural Sciences, Chukwuemeka Odumegwu Ojukwu University, Anambra State
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Egbuna C. An unusual color change in tetracycline HCl powder – from drug to poison. Med J DY Patil Vidyapeeth 2019;12:152-4
| Summary|| |
This report is a wake-up call for the dangers associated with breach in good manufacturing practice (GMP) during the production of tetracycline HCl capsules. Tetracycline HCl (a yellow, odorless, hygroscopic, crystalline, powder) is a broad-spectrum antibiotic used for the treatment of wide range of diseases that is caused by Gram-positive or Gram-negative bacteria, atypical organisms, mycoplasmas, and rickettsiae and some other eukaryotic protozoan parasites. This drug overtime has found extensive use in clinical, veterinary, and agricultural applications. Usually, tetracycline HCl powder are encapsulated and sold by pharmaceutical companies. This sometimes follows an unusual color change from yellow to dark grayish color just within 3–6 months of production which usually go unnoticed by the unsuspecting consumers. The color change is a sign of degradation in which a toxic derivative forms (4-epianhydrotetracycline). A preliminary studies conducted over a period of 3–4 months revealed that the color changes arise from the poor handling of the environmental condition during production process which is a breach of GMP.
| Introduction|| |
Good manufacturing practice (GMP) is a set of practice which ensures that the right procedures in the manufacture of pharmaceutical products are followed. GMP aims at ensuring that the desired quality in maintained. Sometimes, a breach in GMP cannot be detected nor corrected through the testing of the finished product which leads to final products of undesirable quality. Such products become a nuisance to the society causing health problems, market recalls, and huge loss on the part of the manufacturer. To minimize risks, GMP needs to be adhered to.
The focal point of analysis in this paper is the in-house industrial manufacture of tetracycline HCl, a broad-spectrum antibiotic used for the treatment of wide range of diseases caused by Gram-positive and Gram-negative bacteria, atypical organisms (such as chlamydiae), mycoplasmas, and rickettsiae and some eukaryotic protozoan parasites., Tetracycline HCl inhibits protein synthesis by binding specifically to 30S ribosomes and preventing access of aminoacyl tRNA to the acceptor site on the mRNA–ribosome complex. Tetracycline is also useful in disease prevention and control.
Tetracycline HCl powder comprises oxygenated hydronapthacene structure [Figure 1], produced by certain strains of Streptomyces aureofaciens or by other means such as fermentation by semisynthesis., The first tetracycline antibiotic chlortetracycline was discovered in 1948, from the culture broth of a novel species of Streptomyces and since ever has found extensive use in clinical, veterinary, and agricultural applications – 5000 metric tons. Its oxygenated hydronapthacene structure is prone to certain reactions occasioned by environmental factors or poor manufacturing practices which leads to a physical change of its yellow color to dark or brownish color over time.
| Properties of Tetracycline Hci|| |
As specified in the complete drug reference guide, Martindale: USP 31 (Tetracycline Hydrochloride). Tetracycline HCl is “a yellow, odourless, hygroscopic, crystalline, powder. Tetracycline hydrochloride darkens in moist air when exposed to strong sunlight. Soluble 1 in 10 of water and 1 in 100 of alcohol; practically insoluble in chloroform and in ether; soluble in solutions of alkali hydroxides and carbonates, although it is rapidly destroyed by alkali hydroxide solutions. A 1% solution in water has a pH of 1.8–2.8. The potency of tetracycline hydrochloride is reduced in solutions having a pH below 2. Store in airtight containers. Protect from light.”
| The Unstable Nature of Tetracycline|| |
The wide usage and the very sensitive nature of tetracycline HCl calls for caution. From my experience and preliminary assessment of the storage and production conditions of tetracycline HCl in the quality control department of the pharmaceutical company, it is glaring that the poor handling of tetracycline HCl capsule powder often results in changes of the physicochemical properties which is seen by sudden change of the yellow color powder in the capsule to dark grayish color just after 3–4 months of production. This results from negligence or lack of total compliance of GMP practices from raw material handling, filling of capsules, blistering, packaging, and to storage owing to the improper exposure of tetracycline HCl, especially in warm, moist, and acidic environments. With this in mind, even after full compliance, stability test for tetracycline HCl and its degradation product needs to be examined periodically with time. This observations and recommendations came to a satisfactory conclusion based on the results obtained from tetracycline HCl samples subjected to different storage conditions (in airtight container, in airtight container + cold temperature, in airtight container + hot temperature, and tetracycline HCl in moist exposed container which was kept for a duration of 3–6 months.
| Degradation Products and Its Associated Toxicity|| |
The most important of the degradation product of tetracycline is 4-epianhydrotetracycline HCl [Figure 2], a tetracycline impurity D formed from secondary degradation product by epimerization reaction of tetracycline and dehydration at the C6 position to aromatize the B ring., The degradation process can be illustrated in two ways. First, it reversibly epimerizes to 4-epitetracycline which dehydrates irreversibly to 4-epianhydrotetracycline and then reversibly to anhydrotetracycline or that tetracycline irreversibly dehydrates directly to anhydrotetracycline, which reversibly epimerizes to 4-epianhydrotetracycline.
Although 4-epianhydrotetracycline now serves as an important standard for monitoring tetracycline stability, the degradation is associated with a loss of antibiotic activity and enhanced toxicity. The 4-epianhydrotetracycline is considered biologically active and is implicated in tetracycline toxicity. Studies using rats has shown that 4-epianhydrotetracycline causes renal toxicity and a decrease in mitochondrial respiration. Another study shows that 4-epianhydrotetracycline HCl can have a 250-fold higher toxicity depending on the system under study.
| Way Forward|| |
A study by Sigma-Aldrich shows that tetracycline stored for approximately 4 years below 0°C still displayed a single spot by thin-layer chromatography. This shows that tetracycline HCl is stable at low temperature. Pharmaceutical companies, especially those in the tropical regions, should ensure that raw materials and the finished products are kept at low temperature while ensuring dehumidified condition, light, and acidic/alkaline conditions protection during filling of the capsules and other production processes. On the part of the end users, it is recommended that tetracycline drugs should be purchased from trusted sources and that a preliminary check of the color of tetracycline HCl should be done before consumption/administration. Finally, the quality control unit of a pharmaceutical company should optimize assay methods using primary tetracycline HCl and the degradation product standards for easy detection as against the usual ultraviolet spectrophotometric methods
| References|| |
Chopra I, Roberts M. Tetracycline antibiotics: Mode of action, applications, molecular biology, and epidemiology of bacterial resistance. Microbiol Mol Biol Rev 2001;65:232-60.
Pena A, Carmona A, Barbosa A, Lino C, Silveira I, Castillo B, et al.
Determination of tetracycline and its major degradation products by liquid chromatography with fluorescence detection. J Pharm Biomed Anal 1998;18:839-45.
British pharmacopeae. Tetracycline HCl. Electronic, Version 17. TSO (The Stationery Office): UK. 2013.
Sweetman SC, editor. Tetracycline HCl. Martindale, the complete drug reference Guide. 36th
ed. Pharmaceutical Press: London SEl 7JN, UK. 2009. p. 362.
[Figure 1], [Figure 2]