The active pharmaceutical ingredient (API) through polymorphThe active pharmaceutical ingredient (API) through polymorph

The
aim of this study is to improve the physical properties of an active
pharmaceutical ingredient (API) through polymorph and cocrystal screening. The
API investigated is Erlotinib which is found in the anti-cancer drug, Tarceva,
used to treat non-small-cell lung cancer (NSCLC).4 Lung cancer has a
high mortality rate worldwide and NSCLC accounts for approximately 75% of lung
cancers.5 One of the
drawbacks of this drug is that it belongs to Biopharmaceutical
Classification System (BCS)
class II which is characterized by low solubility and high permeability.4 As a result, new
forms having higher solubility would be preferable if bioavailability is to be
improved. Having high solubility ensures that drug is dissolved easily, while
high permeability ensures that drug is completely absorbed in limited time through
the small intestine.6 When drugs have
poor solubility a patient has to take more doses of a tablet, which results in
higher toxicity levels and more side effects.4

Cocrystals
and polymorphs can be used to alter important physical properties of drugs such
as the solubility, stability and bioavailability.7 A polymorph
screen and solubility study are first done simultaneously to try identifying
any new polymorphs of erlotinib and determine the solubility of the API in
different solvents. This is followed by a cocrystal screening of the API using
a number of coformers found on the Generally Recognized As Safe (GRAS) list. Afterwards
characterisation is done to determine if any new polymorphs or cocrystals were
formed using optical microscopy, hot stage microscopy (HSM), Infrared (IR) and
X-ray diffraction (XRD). The last step is solubility testing of any new
cocrystals and polymorphs, to determine whether the solubility has improved.

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Chapter
2. Literature Review

2.1
The API:  Erlotinib

Erlotinib
is a quinazoline derivative also known as
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy) quinazolin-4-amine with a
chemical formula of C22H23N3O4.
Figure 1. Shows the structure of an erlotinib molecule:

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Figure 1: Erlotinib molecule 4

Erlotinib
is made up of various functional groups. In fact, it has a quinazoline attached
to a secondary amine and two ether groups. It also has a phenyl group and a
terminal alkyne. The erlotinib molecule has no stereocenters.

In
the anticancer drug Tarceva, erlotinib is found as a hydrochloride salt and it
acts by inhibiting the activity of the epidermal growth factor receptor (EGFR).8 EGFR is a
transmembrane protein tyrosine kinase which plays a decisive role in signalling
transduction. These regulate important cellular functions such as survival and
proliferation. If an over-expression of EGFR occurs this leads to human
tumours.5 In 2004 Tarceva
was approved by the FDA as an oral anti-cancer drug.9 The product is
presented as film coated tablet containing 25 mg, 100 mg and 150 mg.10 Both erlotinib
and erlotinib hydrochloride are crystalline powders with colour ranging between
white and pale yellow.10

Erlotinib
has a solubility of less than 10 mg L-1 which very low and a high permeability
(log P =2.7). In erlotinib hydrochloride the solubility is improved to 400 mg L-1
but this is still considered to be a low solubility value. Its
bioavailability is also low at 59 %.4  As a result the drug classifies in BCS Class
II. The BCS was created by FDA to characterize drugs into four classes
according to their solubility and permeability.6.