A Review On Doxycycline And It’s Impurities

Doxycycline is a tetracycline broad spectrum and an antibiotic for the treatment of bacterial infections. Doxycycline is also used to treat many diseases like Lyme disease, bacterial pneumonia, typhus, and chlamydia infections, and also for the various infection caused by gram-positive and gram-negative bacteria aerobes and anaerobes and also other types of bacteria.

Doxycycline got patented in 1957 and in 1967 for commercial use. Doxycycline comes under the essential medicines list of the World Health Organization and is also available in different brands at the national and at international levels like Doxycycline by Actavis, Vibramycin by Pfizer, and other brands. Based on the structure some of the derivatives are used for clinical studies like tetracycline, minocycline, oxytetracycline, doxycycline, and metacycline.

Chemical properties of Doxycycline:

Doxycycline exists in different forms like doxycycline monohydrate, doxycycline hyclate, and also other forms like doxycycline hydrochloride and calcium also. Doxycycline Hyclate and doxycycline monohydrate are considered generic antibiotics and approved drugs by the US Food and Drug Administration (FDA); both have different brands and are available in different forms capsules, oral suspension, and tablets. Doxycycline, doxycycline hyclate, and monohydrate are yellow and crystalline powders.

Doxycycline an overview:

The structure of Doxycycline is represented as:

Doxycycline Impurity

IUPAC Name: 4S,4aR,5S,5aR,6R,12aS)-4-(dimethylamino)-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide as mentioned in the literature and  

CAS NO: 564-25-0

Doxycycline is a tetracycline broad-spectrum antibiotic. Antibiotic substances are generally prepared and produced by different methods like fermentation (one or more steps by synthetic method i.e. semi-synthetic substances) and also by chemical synthetic methods. During the manufacturing process of the active substance, the impurity profile is considered the critical part as overall it depends on the manufacturing process and its parameters. There are different analytical techniques that are used to control the impurities at different stages and can be analyzed by column chromatography and other techniques to get the final product purity as per the required pharmacopeia.

The specification and the critical intermediates have limits for the specified and unspecified impurities and also the impurity profile as specified for the final active pharmaceutical ingredient (API). To have control over impurities, process parameters and method of manufacturing recent strategy QbD can be used for development and manufacturing i.e. quality by design QbD. This method helps to ensure that the final drug substance is as per the purity, quality, and other parameters. Quality by design in the manufacturing process has advantages over process controls, analytical techniques, and quality assurance.   

As per the European Medicines and Agency (EMA) mentions the specifications and guidelines for the related impurities in the antibiotics, impurity profile, identifications, and qualification thresholds. As described in ICH Q3A, the guidance describes the impurity profile for antibiotics drug substance for each specified identified and unidentified impurity and for any unspecified impurity with the acceptance criteria of not more than the identification threshold and the total impurities.

As it is very important to control the quality of the final active substance and presently there are various rapid, simple, existing analytical techniques available like a broad-based method of analysis, robust like high performance liquid chromatographic techniques, validation, and also the ICH International Conference of Harmonization guidelines. Several impurities of Doxycycline have been isolated and purified by chemical synthetic method and analytical techniques and are reported and also available at Veeprho: Doxycycline EP Impurity A, Doxycycline EP Impurity B (free base), Doxycycline EP Impurity B (HCl salt), Doxycycline EP Impurity C, Doxycycline EP Impurity D, Doxycycline EP Impurity E, Doxycycline EP Impurity F, Doxycycline Related Compound A” (6-epidoxycycline).

 LIST OF DOXYCYCLINE IMPURITIES:

Doxycycline EP Impurity A 
CAS No.: 41411-66-9
IUPAC Name: (4S,4aR,5S,5aR,6S,12aS)-4-(Dimethylamino)-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide HCl 
Doxycycline Related Compound A (6-epidoxycycline)
CAS No.: 3219-99-6
IUPAC Name.: (4S, 5S, 6R, 12aS)-4-(dimethylamino)-3, 5, 10, 12, 12a-pentahydroxy-6-methyl-1, 11-dioxo-1, 4, 4a, 5, 5a, 6, 11, 12a-octahydrotetracene-2-carboxamide
Doxycycline EP Impurity B (free base)
CAS No.: 914-00-1
IUPAC Name.: (4S, 4aR, 5S, 5aR, 12aS)-4-(Dimethylamino)-1, 4, 4a, 5, 5a, 6, 11, 12a-octahydro-3, 5, 10, 12, 12a-pentahydroxy-6-methylene-1, 11-dioxo-2-naphthacenecarboxamide
Doxycycline EP Impurity B (HCl salt) 
CAS No.: 3963-95-9
IUPAC Name: (4S,4aR,5S,5aR,12aS)-4-(Dimethylamino)-3,5,10,12,12a-pentahydroxy-6-methylene-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide HCl 
Doxycycline EP Impurity C 
CAS No.: 6543-77-7
IUPAC Name: (4R,4aR,5S,5aR,6R,12aS)-4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide 
Doxycycline EP Impurity D 
CAS No.: 97583-08-9
IUPAC Name: (4R,4aR,5S,5aR,6S,12aS)-4-(Dimethylamino)-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide 
Doxycycline EP Impurity E 
CAS No.: 79-57-2
IUPAC Name: (4S,4aR,5S,5aR,6S,12aS) -4-(dimethylamino)-3,5,6,10,11,12a-hexahydroxy -6-methyl-1,12-dioxo-1,4,4a,5,5a,6,12,12a-octahydrotetracene -2-carboxamide / Oxytetracycline 
Doxycycline EP Impurity F 
CAS No: 122861-53-4
IUPAC Name: 4S,4aR,5S,5aR,6R,12aS)-2-acetyl-4-(dimethylamino)-3,5,10,12,12a-pentahydroxy- 6-methyl-4a,5a,6,12a-tetrahydrotetracene-1,11(4H,5H)-dione 

Doxycycline is a tetracycline broad spectrum and an antibiotic for the treatment of bacterial infection. Doxycycline exists in different forms like Doxycycline monohydrate, hyclate, hydrochloride, and calcium. Doxycycline Hyclate and Doxycycline monohydrate are considered generic antibiotics and approved drugs by the US Food and Drug Administration (FDA). European Medicines and Agency (EMA) also mention the specifications and guidelines for the related impurities in the antibiotics, impurity profile, identifications, and qualification thresholds.

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