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Polymorphism Issues

Because polymorphism can have an effect on so many aspects of drug development, it


is
important to fix the polymorph (usually the stable form) as early as possible in the
development cycle and probably before campaign 3. The FDA has produced guidance
for
industry: ANDAs: Pharmaceutical Solid Polymorphism Chemistry, Manufacturing, and
Controls Information (http://www.fda.gov/cder/guidance/7590fnl.htm). Raw et al. (2004)
have reported this in the literature, but the reader should consult the FDA Web site for
the
most up-to-date guidance.
While it is hoped that the issue polymorphism is resolved during prenomination and
early development, it can remain a concern when the synthesis of the drug is scaled up
into a
larger reactor or transferred to another production site. In extreme cases and despite
intensive
research, work may have only produced a metastable form and the first production
batch
produces the stable form. Dunitz and Bernstein (1995) have reviewed the appearance of
and
subsequent disappearance of polymorphs. Essentially, this describes the scenario
whereby,
after nucleation of a more stable form, the previously prepared metastable form could
no
longer be made.
The role of related substances in the case of the disappearing polymorphs of
sulphathiazole has been explored (Blagden et al., 1998). These studies showed that a
reaction
by-product from the final hydrolysis stage could stabilize different polymorphic forms of
the
compound depending on the concentration of the by-product. Using molecular modeling
techniques, they were able to show that ethamidosulphthiazole, the by-product,
influenced the
hydrogen bond network and hence form and crystal morphology.
In the development of a reliable commercial recrystallization process for dirithromycin,
Wirth and Stephenson (1997) proposed that the following scheme should be followed in
the
production of Candidate Drugs
.
1. Selection of the solvent system
2. Characterization of the polymorphic forms
3. Optimization of process times, temperature, solvent compositions, etc.
4. Examination of the chemical stability of the drug during processing
5. Manipulation of the polymorphic form, if necessary
While examples of disappearing polymorphs exist, perhaps more common is the
crystallization
of mixtures of polymorphs. Many analytical techniques have been used to quantitate
mixtures of polymorphs, for example, XRPD has been used to quantitate the amount of
cefepime: 2HCl dihydrate in cefepime, 2HCl monohydrate (Bugay et al., 1996). As noted
by
these workers, a crucial factor in developing an assay based on a solid-state technique
is the
production of pure calibration and validation samples. Moreover, while the production of
the
forms may be straightforward, production of homogeneously mixed samples for
calibration
purposes may not be so. To overcome this problem, a slurry technique was employed,
which
satisfied the NDA requirements, to determine the amount of one form in the other. The
criteria
employed are as follows:
1. A polymorphic transformation did not occur during preparation or analysis.
2. A limit of detection of 5% (w/w) of the dihydrate in monohydrate.
3. Ease of sample preparation, data acquisition, and analysis.
4. Ease of transfer to a quality control (QC) environment.
Calibration samples were limited to a working range of 1% to 15% w/w, and to prepare
the
mixes, samples of each form were slurried in acetone to produce a homogeneous
mixture of
the two.
With respect to solid dosage forms, there have been a few reports on how processing
affects the polymorphic behavior of compounds (Morris et al., 2001). For example, the
effect of
polymorphic transformations that occurred during the extrusion-granulation process of
carbamazepine granules has been studied by Otsuka et al. (1997). Results showed that
granulation using 50% ethanol transformed form I into the dihydrate during the process.
Wet
Preformulation: An Aid to Product Design 209
granulation (using an ethanol-water solution) of chlorpromazine hydrochloride was
found to
produce a phase change (Wong and Mitchell, 1992). This was found to have some
advantage
since form II (the initial metastable form) was found to show more severe capping and
lamination compared with form I, the (stable) form produced on granulation. Using a
range
of compounds, Wikstrom et al. (2008) have studied factors that influence the
anhydrateto-
hydrate conversion during wet granulation and concluded that the transformation was a
function of such things as the compounds solubility, surface properties, seeds, and the
shear
forces involved in wet granulation. However, even this paper noted that better models
were
needed to understand the complexities of the transformations. Solvate formation may
have some advantages. For example, Di Martino et al. (2007) showed that the
desolvated
dioxane solvate of nimesulide had better tableting properties than the known
polymorphs of
the compound, which appears to represent a viable method of improving the
compression
properties of drug substances.
Polymorphism is not only an issue with the compound under investigation, that is,
excipients also show variability in this respect. For example, it is well known that the
tablet
lubricant magnesium stearate can vary depending on the supplier. In one study, Wada
and
Matsubara (1992) examined the polymorphism with respect to 23 batches of
magnesium
stearate obtained from a variety of suppliers. Using DSC they classified the batches into
six
groupsinterestingly, the polymorphism was not apparent by XRPD, IR, or SEM
observations. In another report, Barra and Somma (1996) examined 13 samples of
magnesium
stearate from three suppliers. They found that there was variation not only between the
suppliers but also in the lots supplied by the same manufacturer.
It is well known that polymorphism is a function of temperature and pressure, thus
under the compressive forces that compounds experience under tableting conditions
phase
transformations may be possible. However, Nemet et al. (2005) have sounded a note
of caution
when conducting analysis of compressed samples. They reported that DSC
measurements
tended to amplify the transformation of form B to form A of famotidine.
SOLUTION FORMULATIONS
Development of a solution formulation requires a number of key pieces of
preformulation
information. Of these, solubility (and any pH dependence) and stability are probably the
most
important. As noted by Meyer et al. (2007), with over 350 parenteral products marketed
worldwide, these probably represent the most common solution formulation type. The
principles and practices governing the formulation development of parenteral products
have
been reviewed by Sweetana and Akers (1996). Strickley (1999, 2000, 2001) has
produced a
useful series of papers detailing the formulation of a large number of compounds
delivered by
the parenteral route. A further review by Strickley (2004) has detailed solubilizing
excipients
for both oral and injectable formulations. Rowe et al. (1995) have described an expert
system
for the development of parenteral products (see also chapter 9).
Solubility Considerations
One of the main problems associated with developing a parenteral or any other solution
formulation of a compound is its aqueous solubility. For a poorly soluble drug candidate,
there
are several strategies for enhancing its solubility. These include pH manipulation,
cosolvents,
surfactants, emulsion formation, and complexing agents; combinations of these
methods can
also be used (Ran et al., 2005). More sophisticated delivery systems, for example,
liposomes,
can also be considered.

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