Partnering with the right contractor is one of the most critical decisions a pharmaceutical company can make

The active pharmaceutical ingredient (API) is the foundation of a final drug product and is a crucial consideration when choosing a Contract Development and Manufacturing Organisation (CDMO). To understand API contract manufacturing, first, it is necessary to understand what is meant by an “active ingredient.”

Also called the “bulk active” or “bulk drug substance,” the API is the part of the drug that produces the intended effect in the diagnosis, cure, mitigation, treatment or prevention of disease or that affects the structure or any function of a human or animal. The term includes those components that may undergo a chemical change and be present in a modified form intended to furnish the specified pharmacological activity in a finished drug product.Favipiravir (T-705, 6-fluoro-3-hydroxypyrazine-2-carboxamide) is a novel low molecular weight antiviral compound. It has shown activity against many types of RNA viruses (all strains of influenza А, В, С, arenovirus, bunyavirus, flavivirus, alphavirus, norovirus,as well as the Zika, Usutu,and Ebola viruses). The generally good tolerance of human patients to favipiravir and the high barrier to the development of resistant viral strains indicate that this drug holds great promise for clinical use around the world. It should be noted that a representative of the Zhejiang Hisun Pharmaceutical company from China has anounced that this company has received marketing authorization from the Chinese government for favipiravir as a possible medication against the coronavirus causing Covid-19.

Favipiravir was first synthesized in 2000 by a route consisting of seven steps. The starting material was 3-aminopyrazine-2-carboxylic acid. The amination step was catalyzed by a costly (S)-(–)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl ((S)-BINAP), fluorination required using the highly corrosive Olah reagent, while the overall reaction yield was approximately 0.44%.

Improved methodologies for the synthesis of favipiravir have been reported in recent years. In particular, a fourstep method enabled the synthesis of favipiravir from commercially available 3-hydroxypyrazine-2-carboxylic acid, which was subjected to esterification and amidation. The nitration of pyrazine ring was followed by reduction of the nitro group in the presence of Raney nickel, allowing to minimize the amount of byproducts. After the replacement of amino group with a fluorine atom, the overall yield of the target product 1 was 8%.

Edoxaban versus Warfarin in Patients with Atrial Fibrillation

Edoxaban is a direct oral factor Xa inhibitor with proven antithrombotic effects. The long-term efficacy and safety of edoxaban as compared with warfarin in patients with atrial fibrillation is not known.Nicotinamide Riboside (NR) is a next-generation vitamin B3 that has been found to be naturally-occurring in milk in trace amounts. The metabolism of NR is unique from that of other more commonly known forms of vitamin B3 , nicotinamide and nicotinic acid. Specifically, NR has been shown in a pre-clinical study to be the most effective form of vitamin B3 at increasing nicotinamide adenine dinucleotide (NAD+)2 .

Nicotinic acid (also known as niacin) and nicotinamide (also known as niacinamide) were discovered in the 1930’s to be the factors that cured pellagra . Niacin is known to cause severe flushing . In 2004, nicotinamide riboside emerged as a newly discovered NAD+ precursor and does not bind to the receptor responsible for flushing.

NR has pre-clinically demonstrated that it is superior to both niacin and nicotinamide, both of which are standard forms of vitamin B3 commonly used in vitamin supplements and foods, at boosting NAD+2 . This is due to the fact that NR is not reliant upon a conversion step requiring the enzyme “NAMPT” , see Figure below. The activity level of NAMPT determines the amount of nicotinamide that is converted into NAD+ , which is why this particular step in the process is often referred to as the “rate limiting step”. As normal aging occurs, the activity of NAMPT is thought to decrease. NR can be used by the cell to make NAD+ without this enzymatic step.

Chemical Properties of Nicotinamide

Nicotinamide" target="_blank">http://www.leadpharmaceutical.com/">Nicotinamide riboside (NR) is part of the B3 vitamin family. Like other forms of vitamin B3, nicotinamide riboside gets converted into nicotinamide adenine dinucleotide (NAD+), a coenzyme essential for life. For this reason, it is often called a NAD+ precursor because it is part of the series of chemical steps that are required to create NAD+.
Different biosynthetic pathways are responsible for converting the different B3 vitamins into NAD+. The enzyme nicotinamide phosphoribosyltransferase (Nampt) catalyzes the rate-limiting step of the two-step pathway converting nicotinamide to NAD+. NR kinase enzymes can also function as a salvage pathway for NAD+, but this pathway is not essential.