Handbook of Solvents - George Wypych - ChemTech - Ventech!

986 Michel Bauer, Christine Barthélémy
ondary amines and/or is susceptible to oxidation or hydrolysis, it is likely that degradants
will be formed over the time, reducing potentially the retest date of the raw material. The
same situation could affect the DP and therefore two examples are given in paragraph
14.21.1.3.2.
14.21.1.3.1.4 Solvent purity and crystallization
This issue is may be less known except for chemists working in this specialized area. Because
the consequences can be important for the processability, stability and occasionally
bioavailability of the drug substance in its formulation, it is relevant to comment on this subject.
14.21.1.3.1.4.1 Role of the nature and the quality of solvent on crystallization
Most of the drugs on the market are obtained as a defined crystalline structure and formulated
as solid dosage forms. It is well known that a molecule can crystallize to give different
crystalline structures displaying what is called polymorphism. The crystal structures may
be anhydrous or may contain a stoichiometric number of solvent molecules leading to the
formation of solvates (hydrates in case of water molecules). Pseudopolymorphism is the
term used to describe this phenomenon.
Another characteristic which plays a major role in the overall processability of the DS
for DP manufacture is the “crystal habit”. This term is used 15,16 to describe the overall shape
of crystals, in other words, the differing external appearance of solid particles which have
the same internal crystalline structure.
Both structures (internal, external) are under the control of different parameters including
the nature of the solvent used and its quality. The role of the solvent itself in the
overall crystallization process, including the determination of the crystal structure and the
crystal habit is well known. 17 But it is equally worth noting that impurities coming from:
• the product to be crystallized
• the solvent used
• the environment
can selectively affect the nucleation process and the growth rates of different crystal
faces. 17-21 They can be selectively adsorbed to certain faces of the polymorphs thereby inhibiting
their nucleation or retarding their growth to the advantage of others. Crystal shape
(habit) can also be modified by a solvent without polymorphic change. Additives or impurities
can block, for a defined polymorph, the growth rate of certain faces leading e.g. to needles
or plates. It is possible to introduce deliberately additives to “steer” the crystallization
process. An interesting example of this crystal engineering strategy have been published for
e.g., adipic acid 22 or acetaminophen. 23
14.21.1.3.1.4.2 Solvent-solid association/overview
After the crystallization of the product, solvents must be removed in order to obtain the minimum
amount of residual solvents compatible with safety considerations and/or
physicochemical considerations including stability, processability and occasionally microbiological
quality (see Chapter 16.2). Different situations can be encountered.
14.21.1.3.1.4.2.1 Solvent outside the crystal
The solvent remains outside the crystals at the time of crystal formation. It is adsorbed on
the surface or in the crystal planes. In the first case, the solvent is easily removed. But in the
second case, if a cleavage plane exists, the drying process can be very difficult. Two methods
can be used to try to remove this type of residual solvent almost completely.