Desenvolvimento de novos sais do fármaco adifenina com estabilidade física e química aprimoradas, avaliação da biodisponibilidade e estudos de estabilidade físico-química em formulação
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2022-06-23
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Universidade Federal de Goiás
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Here we have solved the adiphenine solid-state hygroscopicity problem through the preparation
of stable, non-hygroscopic multi component crystal forms thereof. Two new salts of adiphenine
were designed by recognition of intermolecular interactions patterns in the Cambridge
Structural Database (CSD) and pKa rules. Some conformants, Generically Recognized as Safe
(GRAS), namely malic acid, fumaric acid, lactic acid, citric acid and oxalic acid, were selected
for the synthesis of monobasic salts with an adiphenine base, and they had a favorable result
in this two synthesis step, namely, are the citrate and oxalate salts. Crystal structure elucidation
reveals that adiphenine adopts different conformations in our salts and in the literature
hydrochloride one, which is related to different intermolecular arrays. The adiphenine
hydrochloride exhibits a classical high hygroscopicity behavior, which retains water fast from
50% of relative humidity (RH), increasing up to 22% of its initial mass in 90% of RH and a net
mass gain of 5% at the end of the desorption cycle (RH = 0%). In the dynamic vapor sorption(DVS) analysis, it was verified that adiphenine citrate and adiphenine oxalate starts to
incorporate water slowly from 50% and 70% of relative humidity (RH), increasing up to 3.2%
and 2.6% of their initial masses in 90% of RH, respectively. At the end of the desorption cycle
(RH = 0%), the samples retained only 0.12% and 0.08% of water relative to their initial masses.
Notably, both carboxylic acid salts had similar solubility as a function of medium pH, while the
hydrochloride one was more soluble than them by factors ranging from 6.7 (relative to citrate
in pH 1.2) to 28.2 (relative to oxalate in pH 4.5). Nevertheless, them pharmacokinetic
parameters of adiphenine after oral administration of the capsules containing the salt forms did
not reflect these solubility differences, since all adiphenine salt forms can be considered highly
soluble drugs according to Biopharmaceutics Classification System (dose/solubility ratio
<250mL). It was observed that the rats treated with capsules containing adiphenine
hydrochoridrate had an increase in AUC0-∞ (1537 vs 914 vs 991 min μg mL-1
) compared with
rats treated with adiphenine citrate and oxalate capsules, respectively, even though the same
Tmáx (48 min) was observed. The dosage tuning can bring the bioavailability of our salts into
that of the hydrochloride salt, with the advantage of non-hygroscopicity and higher chemical
stability. The study stability was also carried out in a known formulation and the result obtained
confirmed that the new adiphenine salts are more stable when exposed to stress conditions.
The evaluation of the stability of the adiphenine salts in the formulation was carried out in such
a way that it was possible to assess whether the adiphenine salts would withstand certain stress
conditions in the salt form and after being incorporated into the formulation. Under photolytic
and humid thermal stress conditions, the stability of the new adiphenine salts is remarkable,
since the content obtained did not show a sharp drop, in addition, the main adiphenine
degrading agent did not show a high % when compared to commercially available salt. We
highlight, in isolated active pharmaceutical ingredients, the degradation between the
commercially available salt and the new salts is similar with degradation lower than 1.6% when
exposed to wet thermal and photolytic conditions. However, when active ingredients are
incorporated into a formulation, the difference in the degradation process is clear. Since the
commercially available salt degraded 9.5% in the thermal condition and 2.5% in the photolytic
condition in variation the new salts of adiphenine citrate and oxalate degraded 1% and 1.9% in
the thermal condition and 0.7% and 1.0% in the photolytic condition, respectively
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OLIVEIRA, C. M. A. Desenvolvimento de novos sais do fármaco adifenina com estabilidade física e química aprimoradas, avaliação da biodisponibilidade e estudos de estabilidade físico-química em formulação. 2022. 92 f. Tese (Doutorado em Química) - Universidade Federal de Goiás, Goiânia, 2022.