New Automated Purification Strategies for Scale-Up

Posted: December 25, 2017

API Manufacturing and Pharmaceutical Manufacturing

Organic compounds are seldom pure. When isolated from natural sources or prepared by organic reactions, they are usually contaminated with small amounts of other compounds. Before carrying out the qualitative and quantitative analysis of organic compounds that is needed to characterize them, it is very important of purify them.

Purification is a critical step in drug manufacturing, helping to eliminate unwanted materials that can be hazardous or compromise drug efficacy.  While there will always be a certain amount of impurities in Active Pharmaceutical Ingredients (APIs) and New Chemical Entities (NCEs).  The goal for a Good Manufacturing Processes (GMP) facility is to minimize these impurities.

While impurities are a fact of life, the challenge is in identifying them and then performing purification processes to eliminate as many as possible.

Effective Purification Strategies

The most common way to purify solids is by crystallization, which involves using a solvent in which the solid to be purified has low solubility at room temperature but is very soluble at elevated temperatures. The solid is dissolved in the solvent at the boiling temperature and is allowed to cool so that the compound crystallizes out of the solvent in pure form and the impurities stay in the solution. This process is often repeated until the desired purity is reached.

Often, a single crystallization can provide pure compounds of greater than 99% purity. If a solid is too soluble at room temperature in a chosen solvent then a mixed solvent system is used whereby another solvent (anti-solvent) is added to the system.

For compounds which are liquids or oils, we purify them either by distillation or with chromatography.  If a liquid is volatile enough the best approach is by distillation.  Compounds that are too high-boiling are purified by column chromatography; the most common being silica gel chromatography. Other types of chromatography can be employed, such as alumina or reverse-phase chromatography.

The Biotage System

Most purification processes involve labor-intensive and time-consuming isolation and purification processes. Automated systems, however, such as those available from Biotage, are fast joining traditional purification methods, since they significantly reduce the total throughput time required.

Here at PCI Synthesis we use the Biotage® Flash 150 system, which supports batch purification of hundreds of grams of material up to 80% faster than traditional glass columns. We’ve found that Flash 150 is a simple, robust and reliable system, containing everything we need for large-scale separations.

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This automated system is most useful in scale-up of chemicals when speed, as well as accuracy are essential. Bottom of FormBiotage Flash 150 systems safely operate at 100 psi enabling fast flow rates and the use of high viscosity solvents, which enable cleaner, purer fractions in less time and with higher overall product yield.

While traditional glass columns can be used for purification, in a comparison between glass columns and a Flash 150M cartridge, fractions were collected in the glass column in a little more than seven hours, while the Flash 150M cartridge required just 90 minutes. Additionally, the recovery ratio of product from the Flash 150M system was four times that of the glass column. This could result in saving nearly four weeks in development time.

We’re always on the look-out for innovative technologies, such as the Flash 150 System, for improving the purification process and ensuring our final products are as pure and safe as possible.

For articles about impurities, check out Identifying Impurities in APIs, Controlling Impurities In Drug Manufacturing, and At what stage of API development should you start to think about ICH guidelines? For more info about PCI Synthesis and our capabilities, give us a call at (978) 462-5555.

About the Author

Chuck Donovan Project Manager at PCI Synthesis
Dr. Shukla has approximately 15 years of experience in Synthetic Organic Chemistry, Route Scouting and Optimization, API development and CMC activities.

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