Organic Process Research & Development 2001, 5, 508−513
A “ Bottom-Up” Approach to Process Development: Application of
Physicochemical Properties of Reaction Products toward the Development of
Direct-Drop Processes
Chien-Kuang Chen* and Ambarish K. Singh*
Process Research and DeVelopment, The Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 191,
New Brunswick, New Jersey 08903, U.S.A.
Abstract:
using this approach soon after route selection and well in
advance of any scale-up operations.
The “bottom-up” approach to development of direct-drop
processes is a powerful, yet simple, strategy that every process
chemist should consider for the development of efficient, cost-
effective, and environmentally friendly processes. This approach
is aided by a “parallel crystallization” technique, which allows
for rapid identification of multiple solvent systems for the
crystallization of the desired product using a minimal amount
of material and solvent. This “bottom-up” approach is il-
lustrated by several examples where the desired product is
crystallized directly from the reaction mixture.
The “ Bottom-up” Strategy
Figure 1 outlines the steps of this strategy. A few grams
of the desired product are prepared by any available method.
Purified starting materials and product are used to generate
linearity curves (concentration vs area counts) by HPLC or
GC. The solubility of the starting materials, product, and
by-products are determined. Attempts are made to identify
several crystallization solvent systems for the product. The
reaction solvent(s) and solvents for work-up and isolation
are then chosen on the basis of the solubility data of the
starting material, product, by-products, and the crystallization
data of the product. The solvent (or solvent system) of choice
is generally the one in which the starting materials, reagents,
and by-products are very soluble, but the product is not.
Finally, the protocol is tested and fine-tuned by an iterative
process until it is optimized.
Since the “bottom-up” strategy relies on finding suitable
solvent systems for the crystallization of the product, a
systematic approach to rapid screening of crystallization
systems is necessary. This can be achieved by a “parallel
crystallization” technique. This technique allows for the
identification of multiple solvent systems for crystallization,
using a minimal amount of material with minimal effort.
Introduction
Traditionally, a synthetic organic chemist thinks about a
chemical step in a linear sequence from reaction to work-up
(isolation) to purification. The chemist tends to focus more
on “how to conduct the reaction” than on “how to work-up
and isolate the product”, because the chemical reactions are
often performed on relatively small scales where after work-
up, the product is typically purified by distillation or
chromatography. In an industrial setting, however, since a
significant portion of the cost of drug substance stems from
the costs of capital, labor, and waste disposal, it is important
to develop not only safe and robust reaction conditions, but
also efficient and environmentally friendly work-up and
isolation procedures.1
We describe herein a strategy, termed the “bottom-up”
approach, which addresses these process development issues
by focusing on the reaction, work-up, and isolation as an
integrated whole. This approach relies on first gathering
information on the physicochemical properties of reaction
product(s), such as solubility and crystallization character-
istics of the reaction product and by-products, and then using
this information to define reaction, work-up, and purification
conditions. The approach often leads to one-pot processes
where the product is isolated by crystallization directly from
the reaction mixture (direct-drop processes). This “bottom-
up” approach offers several advantages: (1) reduction in the
number of unit operations, (2) reduction in cycle-time, (3)
reduction in solvent usage, (4) reduction in organic and
aqueous waste, and (5) reduction in cost. We recommend
The “ Parallel Crystallization” Technique
There are two types of nucleation, which generally
precede crystallization.2 Primary nucleation occurs with
formation of clusters of molecules at the submicrometer level.
When the concentration exceeds saturation (supersaturation),
the clusters become nuclei. Secondary nucleation is caused
by particles resulting from primary nucleation (or seeds)
which helps to initiate crystallization.
There are many strategies to achieve supersaturation
leading to crystallization, including cooling, evaporation, and
addition of an anti-solvent (nonsolvent). On a small scale, it
is difficult to control the rate of cooling or the rate of
evaporation, but the addition of an anti-solvent in combina-
tion with seeding can be done easily to achieve supersatu-
ration and then to initiate crystallization. Since these
experiments can be done in parallel on a test-tube scale, one
* Corresponding
authors.
E-mail:
and
(1) Anderson, N. G. Practical Process Research & DeVelopment; Academic
(2) Mohan, R.; Boateng, K. A.; Myerson, A. S. J. Cryst. Growth 2000, 212,
Press: San Diego, California, 2000.
489 and references therein.
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Vol. 5, No. 5, 2001 / Organic Process Research & Development
10.1021/op0102114 CCC: $20.00 © 2001 American Chemical Society and The Royal Society of Chemistry
Published on Web 08/16/2001