| dc.description.abstract | Baclofen is a centrally acting muscle relaxant that acts as an agonist of the inhibitory
neurotransmitter gamma-aminobutyric acid (GABA). It is primarily used to treat muscle spasticity
in patients with multiple sclerosis and spinal cord injuries. On the South African market, baclofen
is available in a solid pharmaceutical dosage form (tablets) for oral administration. Despite it
being already commercially available for a relatively long period, very little in terms of the physicochemical
properties of baclofen, is known. Some scientific publications reported that baclofen
exhibited a relatively low bioavailability (40%) due to a narrow absorption window in the upper
gastro-intestinal tract, while other literature articles reported a 70 to 80% bioavailability of
baclofen. To complicate matters even further, baclofen can exist in at least two solid-state forms
namely an anhydrate and a monohydrate, however, there exists almost no information on the
physico-chemical properties of these two solid-states of baclofen and no mention is made towards
how the different hydration levels of baclofen might influence its solubility, stability, and
bioavailability.
In this study, solid state investigations were employed with certain physico-chemical
investigations to determine if different solid-state forms of baclofen exist. Physico-chemical
investigations using different instruments (including differential scanning calorimetry,
thermogravimetric analysis, thermal microscopy, scanning electron microscopy, Fourier-
Transform infrared spectroscopy, X-ray powder diffraction and vapour sorption analysis) were
done on baclofen raw material and the product obtained from recrystallisation with water and
quench cooling. The physico-chemical investigations indicated that baclofen may exist in the
anhydrate and the monohydrate form. However, on further investigation it was found that the
monohydrate only exists in solution or environments where sufficient water is available.
Recrystallisation studies using different organic solvents proved to be unsuccessful and therefore
it was concluded that no other solid-state form of baclofen exists.
Furthermore, the solubility, dissolution and membrane permeability of baclofen in different
solvents and bio-relevant media were investigated to determine the biopharmaceutics
classification system (BCS) of baclofen. Equilibrium solubility concentrations of baclofen
anhydrate in different solvents (acetone, 1-butanol, 2-butanol, ethanol, methanol, 1-propanol and
2-propanol) and different bio-relevant media (water, HCl-, citrate- and phosphate buffer solutions)
were determined. Apparent phase transformations were observed with the solvents: acetone, 2-
butanol and ethanol, however, after further examination by means of Differential scanning
calorimetry (DSC), Fourier-transform infrared spectroscopy (FT-IR) and X-ray powder diffraction
(XRPD) the same physico-chemical properties as for baclofen raw material (anhydrate) was
observed. There was also apparent phase transformation observed within the bio-relevant media.
These transformations could possibly be the formation of salts or salt complexes, however, further investigation would be necessary to clarify the observed phenomena. Additionally, it was
observed that baclofen was highly sensitive to small changes in low pH-levels.
Powder dissolutions were performed on baclofen anhydrate in the different bio-relevant media
(water, HCl-, citrate- and phosphate buffer solutions) using 25 mg baclofen anhydrate and using
sufficient baclofen quantities that would result in saturated solutions. These ‘saturated solution’
dissolutions were performed in an effort to identify possible solution-mediated phase
transformation of baclofen anhydrate.
During this study, the in vitro Caco-2 cell model was used for permeation studies. Caco-2 cells
were originally derived from human colon adenocarcinoma. Despite their origin, Caco-2 cells
grow in culture to form a polarised monolayer with tight junctions and an apical brush border that
differentiate on a semi-permeable membrane that displays similar morphological and functional
characteristics as small intestinal enterocytes. The results obtained for the in vitro permeability
studies (Caco-2 monolayer studies) showed low permeability for baclofen raw material in the
apical to basolateral direction and in the basolateral to apical direction.
This study provided information regarding the physico-chemical properties, solubility and
membrane permeability characteristics of baclofen. The information obtained is adequate to
classify baclofen in class 3 of the biopharmaceutical classification system as well as sufficient
evidence towards possible bio-waiver applications for this drug | en_US |
