The thermal properties of amoxicillin suspension in aqueous solutions were analyzed by differential scanning calorimetry
under various solvent conditions to identify changes in thermodynamic parameters closely related to drug absorption and
pharmacokinetic behavior.
Analysis of thermal profiles of amoxicillin in solid form and in aqueous suspension showed several phase transitions, not
reported previously, which correspond to different transformations in drug integrity induced by temperature. The low
temperature endothermic transition in temperature range 20-50°C is described as associated with decomposition of
crystal-like structure of amoxicillin in liquid suspension, which cooperatively dissembles with increase of temperature.
The low temperature endothermic transition is following exothermic transition in temperature range 60-125°C with a
pH dependent temperature maximum occurring in 80-114°C range. While the maximum temperature for the endothermic
transition is practically independent of the solution pH, the exothermic transition displays strong pH dependence,
decreasing its Tmax as the pH of solution decreased from pH 7 to pH 2.0. During heating of the amoxicillin suspension the
exothermic transition demonstrates a complex character with several maximums occurring on the calorimetric thermogram.
The physical and chemical changes in the amoxicillin are associated with the degradation of amoxicillin, as evident
by the yellowing of the solution as it is heated.
The temperature induced changes observed for the amoxicillin aqueous suspension contrast those reported for the solid
form of amoxicillin where only endothermic thermal transition in temperature range 55-125°C are observed. The latter
is associated with dehydration loss crystallinity of the solid form. Based on comprehensive calorimetric analysis, this
manuscript describes the thermal properties as well as transformations between the different states of amoxicillin during
heating.Amoxicillin trihydrate is a beta lactam antibiotic that has been
used worldwide to treat a broad spectrum of bacterial infections
including the upper respiratory tract, cystitis, peritonitis,
gonorrhea, intra-abdominal sepsis, skin and soft tissue infections. The antibiotic formulations are available in varioussolid and liquid dosages consisting of numbers of excipients to
improve its effectiveness. Reconstitution of amoxicillin powder
for the injection of high doses (250mg, 500mg and 1g) is
considered when the oral route is unsuitable or urgent treatment
of severe infection is required. Unfortunately, due to
the wide variability in the quality of drugs in solid form, their
dissolution and pharmacokinetic profiles may behave unpredictably
under conditions which differ from those tested by
the manufacture. Most of the drugs developed in the pharmaceutical
industry have poor solubility or are practically insoluble
in water.
The low aqueous solubility may result in new
chemical entities which are usually associated with poor parental
and oral bioavailability. Upon reconstitution in aqueous
solution some fraction of drug is solubilized while another
one remains in highly hydrated insoluble forms at concentrations
above the drug’s solubility point. Although, the description
of the thermal behavior of amoxicillin solid polymorphs
has already been given in the literature, their thermodynamic
characteristics in aqueous suspension are not well clarified.
For the category of poor soluble drugs that require reconstitution
from solid form to the injectable liquid, determination
of physicochemical properties, thermodynamic stability and
inter-conversion conditions are essential for optimization of
drug absorption and pharmacokinetics. It has been noted that
differences in solubility may affect antibacterial activity more
than pharmacokinetics.
Therefore it is important for pharmaceutical
practice to know stability and physical properties
of drug molecules and their interactions forming the heterogeneous
mixture of drug suspension to predict its pharmacokinetic
and pharmacodynamic behavior. The presence of
insoluble forms may impact drug permeability at the site of
absorption. The nature of the physical forms of amoxicillin,
which belongs to the category of poorly soluble drugs, plays
a key role in affecting its dissolution from a solid dispersion
when given orally in high doses or parentally.
The aim of this study, therefore, was to investigate specific
changes in the structural arrangement of amoxicillin in aqueous
suspension at different temperatures and to characterize
the physical and chemical states of the drugAmoxicillin trihydrate (Teva Pharmaceuticals, USA) was provided
as a 500mg encapsulated dry powder by the Medical
Unit of NASA Ames Research Center (Moffett Field, CA). The
molecular mass of amoxicillin trihydrate MW = 365.4 g/mol
has been used in this analysis. All reagents used in this study
were of analytical grade (Sigma-Aldrich, Germany). Gly-HCl
buffer was used for preparation of samples with pH 2 and pH
3. Buffers with pH 4 and pH 5 were prepared from sodium acetate.
Buffers at pH=7 and pH=8 were prepared from sodium
phosphate. The pH of buffers and solutions of amoxicillin trihydrate
were measured using a pH meter (IQ Scientific Instruments,
San Diego, USA), calibrated with buffer standards with
error ± 0.02 pH units.
Amoxicillin powder was reconstituted in select buffer solutions
(pH 2-8) at ambient temperature and shaken for an hour
to homogenize the amoxicillin preparations. The preparation
was considered as homogeneous following visual evaluation.
Reconstituted samples can be stored at 4°C temperature
over period of 7 days without any detectable degradation or
changes in solubility as assayed by UV-spectroscopy. For
solubility testing of amoxicillin at different pH values, the suspensions
were filtered through Milipore filter with pore size
0.45mm and its amount of soluble fraction was determined
spectrophotometrically using the molar extinction coefficient
of amoxicillin at 254 nm (ɛAM = 1050 M−1 cm−1). Lambda
35 UV- double beam recording spectrophotometer (PerkinElmer
Inc.) with a 1 mm length quartz cuvette were used for
all absorbance measurements.
The concentration of amoxicillin
was corrected for light scattering when measured spectrophotometrically.
Its value before and after filtration enables
a precise measurement of the soluble and insoluble fraction
under each given solvent conditions.
Calorimetric experiments were performed using a Microcal
VP-DSC microcalorimeter with a heating rate of 1 deg C°/min
and external pressure 32 atm.
The amoxicillin concentration in calorimetric experiments varied
in the range of 0.625mg/ml - 14 mg/ml depending on conditions
of each experiment.
Deconvolution analysis of the excess heat capacity function
obtained in the calorimetric experiments was not performed
due to irreversible, non-equilibrium nature of the transitions.
The amoxicillin in solid powder form was analyzed using conventional
Q100 DSC (TA Instrument, USA). Approximately
2 to 5 mg of each sample was heated in an open aluminum
pan from 30 to 250°C at a scanning rate of 10°C/min under a
stream of nitrogen gas.
An optical microscope Axioskop 2 (Carl Zeiss Microscopy, LLC,
USA) with a digital camera attached to a PC utilizing software
was used to record the images of amoxicillin samples spreading
onto glass slabs.
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