Solid-state chemistry at work
» What are some common problems revealed by solid-state chemistry applications?
The need to investigate the solid-state properties of an API is well-known. Stories of solid forms appearing late in development
or after launch with little or no bioavailability have been widely reported in the literature (11, 12). Since the requirement
to investigate polymorphs was enshrined in the regulatory guideline ICH Q6A in 1999, the pharmaceutical industry has turned
this former problem of solid-form diversity into an opportunity (1). Novel solid forms such as cocrystals and amorphous solid
dispersions are valuable resources in rescuing poorly bioavailable drugs in addition to generating intellectual property.
However, some common problems may arise such as batch-to-batch variability, development of the wrong form, and identification
of polymorphs late in development.
Physical properties can vary widely between batches; sometimes this can be attributed to differences in crystalline forms
or mixtures of amorphous and crystalline forms. Usually, these are first noticed as a failed dissolution test or a poor filtration.
In one client example, batches of API used in preclinical and Phase I studies were found to consist of three polymorphs, amorphous
material, and a suspected hydrate. Variances in particle-size distribution and crystal habit are the most common issues encountered
and suggest that crystallizations at scale are still under inadequate control.
Developing the wrong form.
Delaying the polymorph screen as long as possible is a common cost-saving strategy used by smaller companies, particularly
where poor solubility was not a complication in early-phase work. The delay carries significant risks in late phase. For example,
one company relying on in-house expertise only identified the most stable form late in Phase II, by which point the decision
had been taken to progress a metastable form. At Phase III, it was discovered that a mixture of two metastable forms was being
produced in the plant. Although Almac was able to assist in solving this problem, the late-stage discovery added the cost
of controlling and analyzing the future batches, which would have exceeded the cost of outsourcing a comprehensive screen
at an earlier stage.
Although ICH Q6A requires that a polymorph screen be performed on new drug candidates, it does not specify how much effort
should be applied. The most stable form, polymorphs or solvates, can still appear late in development, sometimes after a client
or contractor has already done a screen. Worse still, screening may not be performed on key intermediates or registered starting
materials, which poses an expensive risk to fixed routes in late-phase projects. For example, one supplier produced an insoluble
stable form of a key raw material for a launched compound on their eighty-sixth plant batch. Generic manufacturers have often
encountered new forms of established compounds, for which no screening data may exist, leaving them scrambling for answers.
Several factors may contribute to these problems. One may relate to a reliance on automated high throughput (HT) screening.
Well plates are prone to cross-contamination, and the number of nucleation techniques that can be automated is limited. The
API is experiencing conditions during processing that are not being mimicked in the screening methodology. Fundamentally,
a diversity of nucleation techniques maximizes the chance of finding new forms and accessing all of these is not possible
with HT screening alone (13).
Another factor relates to increased in-licensing of drug candidates. In their haste to get a product for sale, biotech and
virtual companies can be tempted to delay screening or do it on a limited basis. Fortunately, this approach is gradually changing
to the view that a good solid-state technical package is not only a valuable asset, but also comes with the benefit of new
There may also be a lack of integrated solid-state awareness. The synergy created by having synthetic chemists, solid-state
specialists, and formulators working together cannot be underestimated. The impact of the solid state does not end with the
screening at Phase I. Based on our experience, changes in impurity profiles, processing conditions, and excipients can influence
the solid form of the API, requiring careful monitoring at all stages of drug development.
Patricia Van Arnum is a senior editor at Pharmaceutical Technology, 485 Route One South, Bldg F, First Floor, Iselin, NJ 08830 tel. 732.346.3072, firstname.lastname@example.org