Handbook of Solvents - George Wypych - ChemTech - Ventech!

14.21.1 Use of solvents in manufacture of drugs 989
PEG can also contain peroxides which can initiate over time, the formation of
degradants via an oxidation process. Several publications have dealt with this phenomenon.
30,31
14.21.1.3.2.2 Interaction with the container
When the formulation is a solution which is prepared from water and different organic solvents,
it is mandatory to investigate possible interactions between the medium and the container
especially if the latter is of polymeric nature (PVC-PVDC, polyethylene, etc.) with or
without elastomeric stoppers. A thorough investigation is necessary including:
• an examination of the solution for plasticizers, antioxidants, monomers and
oligomers, mineral impurities, potentially extracted from the container,
• the evaluation of the absorption by the container of components (DS, excipients)
contained in the solution.
In the first case, the migration of impurities into the solution could initiate
physicochemical instability and possibly some potential toxicity.
In the second case, a decrease in the content of the DS and/or some excipient (e.g., organic
solvents added to promote the solubility) could lead to some loss of therapeutic efficacy
and in some case to physical instability (precipitation).
14.21.1.3.2.3 Solvates formation during the solid dosage form manufacture
During the granulation process it is possible that the DS (occasionally the excipient) could
transform into a solvated crystalline structure (solvate, hydrate). During the drying process,
different situations can occur:
• The solvate is poorly stable and the solvent is easily removed leading to either the
original polymorphic form but creating a certain degree of disorder in the crystalline
structure or to what is called a “desolvate solvate” form. In this last case, also named
“isomorphic desolvate”, the desolvated solvate retains the structure of its parent
solvated form. The X-ray diffraction patterns look similar between the parent and
the daughter forms. In this situation we have the creation of a molecular vacuum
which could substantially impact on the stability, hygroscopicity and mechanical
characteristics of the DS and finally of the DP.
• The solvate is stable within the formulation: we then have in a sense a new chemical
entity. The properties of the solvate could be entirely different (solubility, kinetics
of dissolution, stability, processability, etc.) and the consequence could be either
positive or negative. The case where the kinetics of dissolution are affected by the
formation of solvates should always be investigated. Papers on this subject have
been published for molecules such as lorazepam, 32 hydrocortisone, 33 cephalexin, 32
etc.
• Obviously, as in the case of raw materials (14.21.1.3.1.4.2.2.3) clathrate formation
should be considered in order to explain possible batch to batch inconsistency.
14.21.1.3.3 Conclusions
We have seen that the solvent, far from being inert, plays a key role by itself and occasionally
via its own impurities in different ways which are important for pharmaceutical development.
We will now discuss how to set up sound specifications for solvents in relation to
their field of use.