TETRABENAZİNİN BAZİK ORTAMDAKİ ÇÖZÜNME ÖZELLİKLERİNİN KATI DİSPERSİYON TEKNOLOJİSİ İLE ARTIRILMASI

Year 2025, Volume: 49 Issue: 2, 241 - 263, 19.05.2025

Hilal Baş , Fırat Yerlikaya , Füsun Acartürk

https://doi.org/10.33483/jfpau.1568365

Abstract

Amaç: Bu çalışmanın amacı, suda düşük çözünürlüğe sahip bir etkin madde olan tetrabenazinin (TBZ) bazik ortamda çözünmesini artırmak için katı dispersiyon teknolojisinin kullanılmasıdır. Katı dispersiyonların karakterizasyon çalışmaları sonucunda elde edilen bulgular ile katı dispersiyon teknolojisinin TBZ’nin çözünmesi üzerindeki etkileri değerlendirilmiştir. Katı dispersiyon teknolojsinin TBZ’nin bazik ortamda çözünmesini artırmada etkili olduğu sonucuna varılmıştır.
Gereç ve Yöntem: TBZ’nin çözünmesini artırmak amacıyla üç farklı katı dispersiyon formülasyonu hazırlanmıştır. Bu amaçla polimerik taşıyıcılar olarak Soluplus® ve Kollidon® VA 64, yüzey aktif madde olarak Gelucire® 50/13 kullanılmıştır. Bu polimerik taşıyıcılar ve yüzey aktif madde kullanılarak hazırlanan katı dispersiyon formülasyonları sırasıyla KD-1, KD-2 ve KD-3 olarak isimlendirilmiştir. Tüm katı dispersiyonlar, etkin madde ve polimerin 1:1 oranında karıştırılmasıyla elde edilmiştir. Hazırlama işlemi, çözücü buharlaştırma yöntemi ile gerçekleştirilmiş ve çözücü olarak aseton kullanılmıştır. Asetonun, rotavaporda düşük basınç altında ve 55°C su banyosunda buharlaştırılması ile katı dispersiyonlar elde edilmiştir. TBZ miktar tayini yöntemi, yüksek basınçlı sıvı kromatografisi (HPLC) kullanılarak 230 nm dalga boyunda geliştirilmiştir ve analitik yöntem validasyonu yapılmıştır. Katı dispersiyonların termal özellikleri diferansiyel taramalı kalorimetre (DSC) ile 25-250°C aralığında analiz edilmiş; Fourier Dönüşümlü Kızılötesi (FT-IR) spektroskopisi kullanılarak polimer ve etkin madde arasındaki olası etkileşimler incelenmiştir. Katı dispersiyonların TBZ’nin çözünmesini artırmaya olan etkisi, pH 1.2 ve pH 6.8 ortamlarında yapılan çözünme hızı çalışmaları ile değerlendirilmiş, elde edilen numuneler HPLC ile analiz edilmiştir. TBZ’nin katı dispersiyon formülasyonlarından salım kinetiklerinin belirlenmesi için çözünme hızı verilerinden hareketle DDSolver yazılımı kullanılmıştır.
Sonuç ve Tartışma: Katı dispersiyonlar için yapılan TBZ miktar tayini analiz sonuçları, her üç katı dispersiyonda ortalama TBZ miktarlarının %98.31 ile %99.19 arasında değiştiğini göstermiştir. Tüm miktar tayini analizlerinde düşük standart sapma değerleri gözlenmiş ve bu durum ölçümlerin tutarlılığını göstermiştir. Termal analizlerde, TBZ’nin endotermik pikinin 130ºC’de ortaya çıktığı ve amorf yapıya dönüşen katı dispersiyonların endotermik pikin şiddetinde azalmaya yol açtığı belirlenmiştir. FT-IR spektroskopisi ile elde edilen spektrumlar, TBZ’nin farklı taşıyıcı polimerlerle fiziksel veya kimyasal etkileşiminin olduğunu göstermiştir. Katı dispersiyonların TBZ’nin çözünmesini artırmaya olan etkisi çözünme hızı çalışmaları ile pH 1.2 ve pH 6.8 ortamlarında incelenmiştir. TBZ, pH 1.2 ortamında hızlı çözünme göstermiş ve ilk 1 saatte tamamen çözünmüştür. 24 saatin sonunda pH 1.2 ortamında etkin maddenin %98.8’i çözünmüştür, pH 6.8 ortamında ise çözünme daha yavaş (%28.8) gerçekleşmiştir. TBZ’nin pH 6.8 ortamındaki çözünürlüğü düşük olduğu için hazırlanan tüm katı dispersiyonların çözünme hızı çalışmaları bu ortamda gerçekleşmiştir. Hazırlanan tüm katı dispersiyon formülasyonlarının, TBZ’nin pH 6.8 ortamındaki çözünme hızını artırdığı gözlenmiştir. Özellikle Gelucire® 50/13 ile hazırlanan katı dispersiyon formülasyonu (KD-3), 24 saatin sonunda en yüksek çözünme oranına (%85.6) ulaşmıştır. In vitro çözünme hızı çalışmaları sonucunda KD-1, KD-2 ve KD-3 formülasyonlarının salım kinetikleri DDSolver yazılımı ile belirlenmiştir. Değerlendirme sonuçlarına göre her üç formülasyon için en uyumlu modeller Korsmeyer-Peppas ve Weibull kinetikleri olarak belirlenmiştir. KD-1, KD-2 ve KD-3 için Korsmeyer-Peppas modeline ait parametreler sırasıyla, n=0.3351, n=0.3511 ve n=0.3015 olarak belirlenmiştir. Weibull modeline ait parametreler sırasıyla, β=0.4303, β=0.4369 ve β=0.5422 olarak hesaplanmıştır. n değeri 0.5’ten, β değeri 0.75’ten düşük olduğundan, salım mekanizmasının Fick difüzyonuna benzer şekilde gerçekleştiği ve katı dispersiyon teknolojisinin TBZ’nin bazik ortamda çözünmesini artırmada etkili olduğu sonucuna varılmıştır.

Keywords

Çözünme hızı , DDSolver , düşük çözünürlük , katı dispersiyon , tetrabenazin

INCREASING THE SOLUBILITY PROPERTIES OF TETRABENAZINE AT BASIC MEDIUM BY USING SOLID DISPERSION TECHNOLOGY

Abstract

Objective: The aim of this study is to use solid dispersion technology to increase the solubility of tetrabenazine (TBZ) at basic medium. The effect of solid dispersions on the solubility of TBZ, which has low solubility in water, was evaluated by characterization studies of solid dispersions. It was concluded that solid dispersion technology was efficient for the increasing the dissolution of TBZ at basic medium.
Material and Method: In order to increase the solubility of TBZ, three different solid dispersion formulations were prepared. For this purpose, Soluplus® and Kollidon® VA 64 were used as polymeric carriers and Gelucire® 50/13 was used as surfactant. The solid dispersion formulations prepared using these polymeric carriers and surfactant were named as KD-1, KD-2 and KD-3, respectively. All solid dispersions were obtained by mixing the active substance and polymer in a 1:1 ratio. The preparation process was carried out by solvent evaporation method and acetone was used as the solvent. Solid dispersions were obtained by evaporating acetone under low pressure in a rotavapor and in a 55°C water bath. TBZ quantification method was developed using high pressure liquid chromatography (HPLC) at 230 nm wavelength and analytical method validation was performed. Thermal properties of solid dispersions were analyzed by differential scanning calorimetry (DSC) in the range of 25-250°C; possible interactions between the polymer and the active substance were investigated using Fourier Transform Infrared (FT-IR) spectroscopy. The effect of solid dispersions on increasing the solubility of TBZ was evaluated by dissolution rate studies in pH 1.2 and pH 6.8 media, and the obtained samples were analyzed by HPLC. DDSolver software was used to determine the release kinetics of TBZ from solid dispersion formulations based on dissolution rate data.
Result and Discussion: The results of TBZ quantification analysis for solid dispersions showed that the average TBZ amounts in all three solid dispersions varied between 98.31% and 99.19%. Low standard deviation values were observed in all quantification analyses, demonstrating the consistency of the indicating. In thermal analyzes, it was determined that the endothermic peak of TBZ appeared at 130ºC and that solid dispersions transforming into an amorphous structure caused a decrease in the intensity of the endothermic peak. Spectra obtained by FT-IR spectroscopy showed that TBZ has physical or chemical interactions with different carrier polymers. The effect of solid dispersions on increasing the solubility of TBZ was investigated in pH 1.2 and pH 6.8 media with dissolution rate studies. TBZ showed rapid dissolution in pH 1.2 medium and was completely dissolved in the first 1 hour. At the end of 24 hours, 98.8% of the drug was dissolved in pH 1.2 medium, while dissolution occurred slower (28.8%) in pH 6.8 medium. Since the solubility of TBZ in pH 6.8 environment is low, the dissolution rate analysis of all prepared solid dispersions was carried out in this environment. It was observed that all prepared solid dispersion formulations increased the dissolution of TBZ in pH 6.8 environment. Especially, the solid dispersion prepared with Gelucire® 50/13 (KD-3) reached the highest dissolution rate (85.6%) at the end of 24 hours. As a result of in vitro dissolution studies, the release kinetics of KD-1, KD-2 and KD-3 formulations were assessed by DDSolver software. According to the evaluation of the results, the most fitted models for all three formulations were determined as Korsmeyer-Peppas and Weibull kinetics. The parameters of the Korsmeyer-Peppas model for KD-1, KD-2 and KD-3 were calculated as n=0.3351, n=0.3511 and n=0.3015, respectively, and the parameters of the Weibull model were calculated as β=0.4303, β=0.4369 and β=0.5422, respectively. Since the n value is less than 0.5 and the β value is less than 0.75, it is concluded that the release mechanism occurs similar to Fick diffusion and solid dispersion technology is efficient for the increasing the dissolution of TBZ at basic medium.

Keywords

DDSolver , dissolution , low solubility , solid dispersion , tetrabenazine

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