Crystal Engineering-Optimization of a Generic Drug Synthesis

Improved Crystallizability of Intermediates

A generic version of a drug is often prepared following different chemistry from that used by the originator. This may arise because some of the intermediates in the originator’s process may be still protected by patents while the drug substance itself can have become free to use. so the generic route must proceed by a new route that avoids the patented intermediates. Such a process would have been worked out for the API provider by its chemists. Although the route may be ‘optimized’ according to what can be done in the laboratory, it is not optimized for the scaled up version. One of the areas where improvements can be made without changing the overall chemistry including the trace solvent analysis, is to make improvements in the efficiency of crystallization of isolated intermediates.

By this I do not mean improvements in the crystallization yield because changes in the crystallization solvent or in the degree of precipitation of the product can have unacceptable effects, in the former case, on the trace solvent analysis and in the latter upon the level of impurities.

I am thinking here of reducing the time for crystallization and filtration. These improvements can be particularly significant for crystallization of intermediates from the early steps of the process where the number of batches of each step can be large. Yet, starting out, synthetic chemists attach little importance to the time spent crystallizing, filtering or drying before they have matured into process chemists.
The size and shape of crystals of a process intermediate are the main factors determining the rate of filtration, the efficiency of washing away impurities, and the rate of drying of the solid.

Crystal Habit Modification for Pharmaceuticals

CA2509796 (WO2004064806A2; US20060122265A1)

PROCESS FOR MODIFYING DRUG CRYSTAL FORMATION

Published 2004-08-05

The patent application teaches a method increasing the bulk density of acicular (needle-like) crystals by cyclical temperature programming of a solid only partially dissolved in a recrystallization solvent.

Generic API manufacturers may be missing out both on a competitive advantage and a cost reducing methodology by not working to control the crystal habits of the general products they manufacture.

CA2509796 (WO2004064806A2; US20060122265A1) is from a family of patent applications filed by Novartis. The alleged invention proposes to use a cycle of temperature fluctuations applied to the recrystallized slurry of a pharmaceutical product to convert needles into more compact solid forms.  The general claims of these applications are unlikely ever to issue. The authors have adopted the strategy of ignoring the prior art rather than trying to distinguish themselves from it.  Novartis is attempting to monopolize something closely akin to the ancient technique called aging, digestion, or Oswald ripening which is known to produce more easily filterable precipitates. This method has been routine in gravimetric analysis for a very long time. I learned it in my undergraduate days reading Inorganic Vogel.

Some additional time ‘ripening’ a product before filtration can more than pay for itself in shorter filtration and drying times. Saving time in a drying step can save plenty of energy. Additionally ripened crystals frequently contain lower levels of impurities.