Conjunctivitis (known as ‘pink eye’) is the infection or inflammation of the conjunctiva—the mucous membrane that covers the eye’s outer surface. In the United States, this uncomfortable ophthalmic condition affects an estimated 6 million people annually, accounting for one percent of all primary care visits.

It usually starts with inflammation, burning, and itchy eyes. It may present as a cold, or upper respiratory infection. Vision blurring and tearing are also common symptoms.

There are several varieties of conjunctivitis, including viral, bacterial, and allergic. While viral conjunctivitis constitutes about 80% of infectious cases and bacterial conjunctivitis accounts for up to 75% of pediatric conjunctivitis diagnoses, allergic conjunctivitis is the most prevalent form of the condition. In the U.S. alone, the allergic condition affects 15 to 40 percent of the population, presenting most frequently in spring and summer when seasonal allergens peak.

However, only a fraction of sufferers seek medical care. Consequently, the condition is frequently underdiagnosed and undertreated, and the actual number of allergic pink eye sufferers could be much higher.

With the incidence of allergic ocular disease continuing to climb, a direct link to a single, sole contributor has not yet been established. But experts believe multiple factors – pollution, genetics, household pets – may contribute to the increasing prevalence.

Treatment of Allergic Conjunctivitis with Antihistamines

Among pharmacological treatments, antihistamines have been shown to successfully treat flair-ups as well as chronic symptoms. Histamine blockers effectively address the inflammatory response that is secondary to the allergic occurrence.

In the past, oral antihistamines were the drugs of choice for allergic conjunctivitis because of their effectiveness in controlling allergic symptoms. However, concerns over negative side effects have made the first-generation drugs less preferable when compared to topical antihistamine applications, such as Alcaftadine. The second-generation agents offer faster relief, greater efficacy, and fewer side effects.

What Is Alcaftadine?

Chemically, Alcaftadine is identified as 6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine-3-carboxaldehyde and is classified as an H1 histamine receptor antagonist.

The medication is applied as a .25 percent ophthalmic solution that is dropped directly into the eye once daily to help stop ocular irritation.

Alcaftadine was first approved by the FDA in 2010 under Allergan’s tradename ‘Lastacaft.’ Within 2 years, sales exceeded those of Elesta, another prescription ophthalmic antihistamine. A number of studies have shown (here and here, for example) that Alcaftadine may offer greater symptom relief than other second-generation antihistamines.

Challenges of Alcaftadine Manufacturing

Multiple challenges are associated with the traditional method of synthesizing Alcaftadine. Among them:

• Time: The manufacture employs a lengthy 8-step process that uses column chromatography to isolate the hydroxymethylated alcohol product.
• Safety: Carcinogenic benzene is incorporated as a solvent.
• Low yield: The process offers low overall yields of the active pharmaceutical ingredient (API) Alcaftadine.
• Expense and complexity: Platinum is used as a catalyst, requiring additional purification and cost.

The impact of these various challenges can be dramatic, from raising manufacturing and process safety costs to lengthening synthesis cycles.

Novel Method Overcomes the Challenges of Alcaftadine Synthesis

Neuland scientists have developed a novel route of synthesis (ROS) to address each of the areas of concern identified above.

In this Asian Journal of Chemistry article, we discuss the scalability and cost effectiveness of our double oxidation strategy which avoids chromatographic purification. (Neuland has filed a US DMF).

The new methodology eliminates the time-consuming chromatographic purification step—utilizing two oxidation reactions instead. Toluene, rather than benzene, is used as a solvent.

With our approach, the overall product yield increases from 6.7% in the traditional process to 20% while eliminating the use of platinum.

To ensure that the Alcaftadine API meets International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) purity standards, we identify and remove any impurities that were created during the synthesis.

The Search for a Technique to Remove Diol Impurity

A key challenge during process development was removal of the diol impurity and unreacted Stage-III from the reaction mixture. The original method was recrystallization, but yields were low and other solvents aside from acetone resulted in a sticky reaction mixture.

We worked through a number of methods, including purification via column chromatography using silica gel (neutralized with triethyl amine) and complete oxidation of the crude reaction mass.

Ultimately, these experiments led our team to a process using two oxidation reactions instead of column chromatography – with ~20% overall yield from Stage-III, versus the product patent yield of ~6.7%.

Neuland’s Cost Effective & Ready-to-Scale Double Oxidation Process

Neuland’s technique uses manganese dioxide (MnO₂) in an effective yet simple double-oxidation process. To perform the synthesis, we partially oxidate hydroxymethylated crude mass using a relatively small amount of MnO₂. This oxidation eliminates the diol impurity and facilitates the alcohol crude crystallization.

Subsequently, we perform a secondary oxidation by adding additional MnO₂ to produce Alcaftadine. This approach to Alcaftadine synthesis prioritizes quality, while delivering significant improvements in process efficiency, speed and commercial sustainability. Neuland has successfully completed three process validation batches, has filed a US DMF (No. 28277). This novel technique has received patent approval in India and is patent pending in the U.S.

Read the peer-reviewed Asian Journal of Chemistry article here > Investigation of Alcaftadine using a Double Oxidation Process by Eliminating Column Chromatography.

Do you have a complex pharmaceutical chemistry challenge you need to solve? Neuland can help! Contact us today to discuss your next API project or to learn more about Neuland’s novel Alcaftadine process.