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Physical chemical properties of selected pharmaceutical co-crystals
Author(s)
Kilinkissa, Ornella Edlyne Youdaga
Date Issued
2014
Type
Thesis
Publisher
Cape Peninsula University of Technology
Abstract
The solid state modification of a given active pharmaceutical ingredient is a desired way to
alter its physicochemical properties, such as solubility or bioavailability. The solubilitymelting
point relationship of the ensuing co-crystal or salt is not fully understood.
In this thesis, a series of model co-crystals and pharmaceutical co-crystals and salts of
baclofen were investigated. The model co-crystals were prepared from 4,4’-bipyridine (BIPY)
and 1,2-bis(4-pyridyl)ethane (ETBIPY) used as host compounds which were combined with a
series of carboxylic acids as co-formers, such as p-toluic acid (PTA), rac-phenylbutyric acid
(racPBA), racemic and S-phenylsuccinic acid (racPSA and S-PSA, respectively). In the
second part, six new multicomponent crystals of baclofen (BAC, (RS) 4-amino-3-(4-
chlorophenyl)-butanoic acid), were prepared with mono- and dicarboxylic acids: two
pharmaceutical co-crystals obtained with benzoic acid (BAC•BA) and p-toluic acid
(BAC•PTA) and four pharmaceutical salts with 1-hydroxy-2-naphthoic acid, (BAC+)(HNA-),
oxalic acid, 2(BAC+)(OA2-), maleic acid, (BAC+)(MA-) and p-toluene sulfonic acid,
(BAC+)(PTSA-)•IPA. The compounds prepared were analysed by single crystal and powder
X-ray diffractometry, differential scanning calorimetry and their solubility was measured in
water and ethanol.
From the analysis of the model co-crystals it was concluded that their aqueous solubility is
inversely related to the melting point values and this can be explained by packing features.
Also, the introduction of a chiral building block, compared to its racemic counterpart, is a
valuable way to limit the formation of the intermolecular interactions in the new
multicomponent crystal and thus decrease the efficiency of the packing which eventually
leads to lower melting points and better solubility.
The analysis of the baclofen crystals suggests that a strong, robust and predictable hydrogen
bonding network with a combination of molecular building blocks which show acceptable
molecular flexibility is a good recipe for successful co-crystal design.
alter its physicochemical properties, such as solubility or bioavailability. The solubilitymelting
point relationship of the ensuing co-crystal or salt is not fully understood.
In this thesis, a series of model co-crystals and pharmaceutical co-crystals and salts of
baclofen were investigated. The model co-crystals were prepared from 4,4’-bipyridine (BIPY)
and 1,2-bis(4-pyridyl)ethane (ETBIPY) used as host compounds which were combined with a
series of carboxylic acids as co-formers, such as p-toluic acid (PTA), rac-phenylbutyric acid
(racPBA), racemic and S-phenylsuccinic acid (racPSA and S-PSA, respectively). In the
second part, six new multicomponent crystals of baclofen (BAC, (RS) 4-amino-3-(4-
chlorophenyl)-butanoic acid), were prepared with mono- and dicarboxylic acids: two
pharmaceutical co-crystals obtained with benzoic acid (BAC•BA) and p-toluic acid
(BAC•PTA) and four pharmaceutical salts with 1-hydroxy-2-naphthoic acid, (BAC+)(HNA-),
oxalic acid, 2(BAC+)(OA2-), maleic acid, (BAC+)(MA-) and p-toluene sulfonic acid,
(BAC+)(PTSA-)•IPA. The compounds prepared were analysed by single crystal and powder
X-ray diffractometry, differential scanning calorimetry and their solubility was measured in
water and ethanol.
From the analysis of the model co-crystals it was concluded that their aqueous solubility is
inversely related to the melting point values and this can be explained by packing features.
Also, the introduction of a chiral building block, compared to its racemic counterpart, is a
valuable way to limit the formation of the intermolecular interactions in the new
multicomponent crystal and thus decrease the efficiency of the packing which eventually
leads to lower melting points and better solubility.
The analysis of the baclofen crystals suggests that a strong, robust and predictable hydrogen
bonding network with a combination of molecular building blocks which show acceptable
molecular flexibility is a good recipe for successful co-crystal design.
Additional information
Thesis (MTech (Chemistry))--Cape Peninsula University of Technology, 2014
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