Alchem granted COS by EDQM for solving stability challenge for micronized digoxin

Alchem International, a privately held pharmaceutical company focusing on the production of plant-derived active pharmaceutical ingredients (APIs), yesterday announced the award of European Certificate of Suitability (COS) by the European Directorate for the Quality of Medicines (EDQM) for its innovative manufacturing process for micronized Digoxin overcoming stability, regulatory and formulation issues for generic manufacturers of digoxin tablets.  

Speaking from Alchem’s European offices in Geneva (Switzerland) Raman Mehta, Alchem CEO and President, commented “Whilst generic formulations of digoxin compared to the originator product Lanoxin have had to compromise to date on bioavailability and dissolution due to stability issues with micronized digoxin the process innovations of our R&D team have removed these barriers”.

He continued, “Our customers are now able to formulate digoxin at the optimum particle sized distribution (PSD) with a molecule that is stable for transport and 1 year at ambient temperatures (15-25oC) and 3 years under cold storage (3-8oC).  We fully expect the shelf life to be extended to 5 years based on ongoing stability studies providing a clear advantage for handling and formulation”.

Digoxin is a specialist drug administered either orally or intravenously to treat various heart conditions including atrial fibrillation, atrial flutter, and heart failure.  Digoxin has a low and narrow dosage range that is patient specific and must be calculated depending on medical condition, age, weight, gender and creatinine clearance.

As a result of this patient specific and low and narrow dosage range (tablets normally contain only 62.5mcg per tablet) the production of the oral dosage forms presents a particular challenge to pharmaceutical manufacturers to achieve homogeneity, dissolution and optimum bioavailability.

Specific research on digoxin formulation published in The European Journal of Clinical Pharmacology1 supports that particle size is an important determinant of the dissolution rate and bioavailability of digoxin. The study demonstrated that the bioavailability of digoxin in tablets with particle sizes of 7 mu or 13 mu was 78-97% of that of digoxin in solution whilst tablets with larger particle sizes show markedly lower bioavailability. Tablets with the largest particle size (102 mu) were only 39% bioavailable compared to the reference solution.1,2  

The importance of particle size is confirmed by the category originator Lanoxin which utilizes a particle size distribution (PSD) of 10 μ: NLT 85%, 20 μ: NLT 95%, 30 μ: NLT 99%.  Whilst post production micronization of digoxin can and has been employed by some API manufacturers to attempt to mimic the specification it cannot achieve the same PSD range and post production micronization also compromises the stability of the active ingredient (API).  In addition, regulatory authorities – such as EDQM – do not accept post production micronization on APIs if not fully described in the API dossier (DMF) or COS (CEP) as it potentially changes the structure, integrity and stability of active ingredients.

Alchem has addressed these challenges by revisiting the production process to achieve the target PSD in stream, during the production process, rather than post production to provide a stable molecule.  The issuance of a COS (CEP) following an assessment and GMP audit by EDQM demonstrates the new production process’ capability and robustness and the process is now subject to a patent filing.

1. Jounela AJ et al. Eur J Clin Pharmacol 1975;8:365-70.
2. Johnson BF et al.  Br J Clin Pharmacol. 1978;5:465-7.