-By Girish Malhotra, PE
President, EPCOT International

Alphabets are the basic building blocks of any language. Our collective proficiency in them allows us to express ourselves to others. Similarly, in the pharmaceutical manufacturing industry, we have to have complete command of its unique alphabet in order to successfully design and manufacture drugs.

The first letter of the pharmaceutical alphabet is “A” which stands for “accountability”. A drug has to have a consistent quality to cure a disease. Pharmaceutical companies have done an excellent job in mastering the first alphabet of its language.

The second letter in our pharmaceutical manufacturing language is "B". In this language the "B" stands for "batch". It is the prevalent manufacturing methodology of pharmaceutical companies worldwide. Over the years, pharmaceutical companies have given us consistent quality drugs by following the “quality by analysis (QBA)” manufacturing mantra. This mantra has worked but can be much more efficient.

In recent years, regulatory bodies and pharmaceutical companies, have coined myriad new TLA's (three letter acronyms) for the pharmaceutical world. These acronyms are intended to move the manufacturing technology from “B” to “C”.

“C” in the pharmaceutical manufacturing alphabet stands for “continuous”. Moving from “B” to “C” seems to be harder than an Everest climb. Should moving from a batch to a continuous process be such a monumental feat? The answer is an unequivocal no.

Many companies have apprehensions about making this change because there is this inherited fear of cost and regulatory hurdles that comes with thoughts of changing after a manufacturing process is approved by regulatory agencies. The truth is, no one knows the costs of re-approval and the size of these hurdles, so these projected apprehensions seem to be self inflicted.

We can have an excellent chemistry for an active pharmaceutical ingredient (API) but if the chemistry and the interaction of chemicals are not understood and are not properly translated to an efficient commercial process, the process will produce quality product only after repeated in-process analysis. For an efficient process, we need to have a quality by design (QBD) process.

Verification of the quality of intermediates is a batch process phenomenon, and is perhaps the biggest hurdle to overcome in order to lead to any manufacturing technology enhancement. API intermediate isolation and their analysis has become the routine of the day. Since the pharmaceutical industry has lived with batch processes for many decades, the comfort of staying at “B” is understandable. Intermediate isolation also suggests that the principles of chemistry and chemical engineering practices are not completely understood and applied to the manufacture of APIs. Had they been understood we would have had a continuous process for API manufacture a long time ago and we would not be isolating intermediates for their quality check.

Elimination of Intermediate Isolation-->QBD-->Continuous Process

In order for the industry to move to a continuous process, it has to have a process that will produce an intermediate of the highest and most consistent quality. By accomplishing this there would be no need to isolate the intermediate and in-process testing would be reduced to a bare minimum. Once intermediate isolation is stopped, it would be a clear indication that the pharmaceutical industry understands chemistry, chemicals and their interaction. It will be a quantum leap toward improving batch processes and a giant first step toward the development and commercialization of a continuous process for the manufacture of API and formulated products.

Move from a batch to a continuous process has to be initiated by an API manufacturer and/or a formulator. If a continuous process for a product is presented for regulatory approval, my conjecture is that it would be handled with kid gloves and expediency. It would be a celebration.

It is the job of the chemist/chemical engineer to understand the nuances and mechanism of chemical reactions and create a simple batch or a continuous manufacturing process. Their forte is to create a process that is economical, safe, meets regulatory requirements and produces consistent quality product from the start. Pharmaceutical companies have to determine ideal candidates for a continuous process.

US patents 6,875,893 and 7,057,069 “process for the manufacture of 2-(benzhydrylsulfinyl) acetamide” [Modafinil] are reviewed. The chemistry outlined is an excellent candidate for a continuous process. The chemistry is as follows.

Modafinil Reaction Mechanism
Step 1:Benzhydrol + Thiourea + HBr--> S-benzhydrylthiouronium bromide + H2O

Step 2:S-benzhydrylthiouronium bromide + KOH --> Benzhydrylthiol + KBr + Urea

Step 3:Benzhydrylthiol + chloroacetamide+ KOH --> 2-(benzhydrylthiol) acetamide + KCl +H2O

A phase separation is needed at this point.

Step 4:>2-(benzhydrylthiol) acetamide + Acetic acid + H2O2 --> 2-(benzhydrylsulfinyl) acetamide

The process stoichiometry for the chemistry described in the patents is compared with the theoretical stoichiometry in Table 1(click to view). For a batch process, one could expect the ratios described. However, they present process simplification, improvement and raw material optimization opportunities.

Step 1 of the reaction is carried out either in tetrahydrofuran (THF)/water or monochlorobenzene (MCB)/water mix. The suggested reaction temperature is about 70°C. But, this reaction cannot be carried out at 70°C as THF/water azeotrope at 65°C. MCB/water azeotropes at 90.2°C. THF is water-soluble whereas MCB is insoluble in water. It is preferable to carry the reaction with MCB/water, as its azeotrope temperature is higher than the THF/water azeotrope. Higher temperature also accelerates the reaction rate. Another alternate would be toluene. Its azeotrope temperature is about 85°C and it is a cheap solvent. If there are any other solvent/water mixes that have a boiling point higher than 70°C, they can be considered.

Solid raw material addition adds to the process complexity. It would be preferable if the solids chemicals are soluble in a solvent of choice. Benzhydrol is not water-soluble. It should be dissolved in a solvent. Thiourea is water soluble. By solubilizing the two reactants in their respective solvents, we have three liquid raw materials. Their feed rate can be controlled and the outlined reaction can be executed with ease. Now, we have the makings of a QBD process as we can control the feed rates and temperature conditions of a batch or a continuous process step. Sequential addition along with sufficient residence time and temperature control will produce the S-benzhydrylthiouronium bromide. Water is produced in the reaction and it can be azeotroped to minimize the reactor volume and control reaction conditions.

Patents suggest different solvents, acids and reaction conditions. Economics and the total reaction process has to be reviewed for chemical selection. Review of reaction mechanism and rates, process conditions and costs is necessary to have an optimum process.

In step 2, thiol is hydrolyzed with an alkali. Again, it is an all liquid process and easy to manage and control. Alkali selection for the hydrolysis should be based on reaction kinetics, cost and safety. Thiol produced is processed in the next step.

Step 3 again is a temperature and residence time driven reaction. Chloroacetamide solution in water provides an excellent opportunity to control the process. After the reaction is complete, the phases are separated by taking advantage of the physical properties to facilitate the process.

Step 4 is an oxidation step and the neutralization of any excess oxidizing agent is an all-liquid process. Purification and crystallization are routine unit operations in the chemical industry.

In each of the above reaction steps, one has to drive the reaction to completion. This minimizes impurities and gives the process a high yield. Batch process stoichiometry due to its nature necessitates an excess of raw materials. Though the patents suggest that the reaction can be done in a single reactor (batch process), this chemistry is ideal for a continuous process. If all of the process conditions are controlled and monitored, intermediate isolation would not be necessary. Patents (‘893 and ‘069) indicate that the yield using THF is higher than using MCB. Proper solvent and process condition selection will result in high yield process. Commercially available process control technologies and equipment can be used to have precise control of reaction stoichiometry and process conditions to have an excellent process. Economics will lead to the best process.

A schematic of a continuous process is illustrated in Figure 1.

Figure 1
T1 to T5 are the raw material tanks. Loop reactors with necessary residence time have appropriately sized pumps and heat exchangers. Oxidation takes place in Rx and the product is filtered and crystallized. Development of a continuous process for Modafinil with the chemistry outlined in these patents can be done concurrently with the development of a batch process. This particular chemistry would take about 4-6 weeks to prove the concept for a continuous process. A commercial process could be designed quickly by chemical engineers who are well versed in the design of such processes. USP 4,177,290, 6,649,796, 7,057,068 and 7,186,860 present other iterations of the Modafinil chemistry.

Going back to the underlying question of why we hesitate to have a continuous process - should we have hesitation for a continuous process? The answer is no.

The reason we do not have continuous processes for APIs is that we have chosen not to have such a process. Companies are using intermediate isolation and their quality check as a “security blanket” for the manufacture of APIs. Pharmaceutical manufacturers need to be weaned from this blanket. The only way this can happen is through a complete understanding of the process chemistry and how to translate it into an effective commercial process. In addition, companies are afraid of the demons of change, regulatory review and inspection warlords and the unknown balance of expense and savings. Regulatory agencies need to create consistent standards of review and inspection using personnel who are well versed with manufacturing simplifications and practices. Companies have to make sure that the product efficacy and other product characteristics (e.g. impurity profile) are as good and/or better than the approved product. It can be a win-win situation.

Certain analgesics are being produced by continuous processes by the specialty chemical companies rather than by the pharmaceutical companies. Opportunities are there and we just have to take advantage of them. In the United States to play, we have to get up to the baseball plate, in Britain and other Commonwealth countries we have to get on the cricket wicket and in Europe and other countries we have to kick the football. Bottom line, if we understand the game, we can champion it. Therefore, let us master and play the game to be the best and have a great game.

About the author:Girish Malhotra, PE, is the President of EPCOT International ( based in Pepper Pike, Ohio. He can be reached via email:, or phone: 216-292-0626