Ultrasound‐Assisted Anti‐Solvent Crystallization of Telmisartan Using Dimethyl Sulfoxide as Organic Solvent

Abstract

In recent years, ultrasound assisted anti‐solvent crystallization has emerged as an excellent approach to reduce the particle size of poorly water‐soluble drugs, thereby achieving improvement in the solubility and bioavailability. In the present study, this concept is employed for telmisartan by studying various critical parameters like the effect of sonication time, sonication amplitude, drug solution concentration, solvent to anti‐solvent ratio, injection rate and crystallization temperature. The particle size of the commercial telmisartan is reduced from 10 µm to 200 nm by anti‐solvent crystallization method by applying 60% ultrasound amplitude for 15 min with 10 mg mL−1 drug concentration, 1:3 of solvent to anti‐solvent ratio, and 10 mL min−1 of injection rate at 30 °C. Physicochemical characteristics; morphology, crystalline structure, the presence of other chemical compounds, enthalpy change, and the melting point of a recovered drug are analyzed using various analytical tools. It is possible to achieve nanoparticles of telmisartan by symbiotic effect of sonication with anti‐solvent crystallization.

Antisolvent Crystallization of Telmisartan Using Stainless-Steel Micromixing Membrane Contactors

“…The crystallization of an organic system has a nucleation order greater than that of the growth order, b ≫ g, which results in growth favored at lower supersaturation with fewer larger crystals. This can be seen from the D [4,3] values going from 13.6 ± 0.6 to 19.9 ± 0.3 μm. The average CSD curves show that a membrane with 5 μm resulted in crystals that had wider distribution with a distinguishable second peak, indicating that agglomeration had occurred which could be attributed to higher droplet/ crystal production that resulted in agglomeration.…”

“…A lower DP flow rate will result in the amount of solvent in the overall flow decreasing and the volume fraction of CP increasing, leading to rapid supersaturation, which for a continuous AXF system was estimated to be 6.55 g L −1 . 50,51 Although a DP flow rate of 58 mL min −1 shows the largest D [4,3] value at 16.02 ± 0.6 μm, it also had the tightest CSD and the highest volumetric productivity of 6.67 mg mL −1 of precipitated amorphous TEL. The CSD curves for 29 and 15 mL min −1 showed multiple peaks, resulting in a variety of different TEL crystal sizes.…”

“…2,8 Various methods have been used to decrease the particle size of API crystals, such as milling, spray drying, sonication, and high-pressure homogenization. 3,9 However, such techniques are energy-intensive, not cost-effective, often result in poor batch-to-batch reproducibility 6 as well as thermal degradation, 9 and have broad crystal size distribution (CSD). 10 Cooling crystallization is the most common method used in industry for the improvement of solubility and can be performed as a batch and continuous process.…”

“…Telmisartan (TEL) (Figure ) is an angiotensin II receptor antagonist, often used to treat hypertension and heart failure. According to the Biopharmaceutical Classification System (BCS), it is classified as a type II drug and therefore exhibits poor dissolution rates, water solubility (9.9 μg/mL), , and bioavailability (40–58% dosage-dependent) similar to many active pharmaceutical ingredients (APIs). Such characteristics pose an issue when it comes to dosage formulations.…”

Improved Crystallization of Ampicillin Trihydrate Based on the Use of Ultrasound

“…The results indicate that the mean size reduction amounts to 95.68% reduction in the presence of ultrasound, i.e., from 89.77 to 3.88 μm, under the optimum condition of power established in terms of yield. A further increase in power resulted in a decrease in yield with similar size reduction, 33 meaning that it is important to dissipate the optimum power during the operation. The original AT sample contains around 80% of crystals within the size range of 20 to 500 μm, whereas AT recrystallized using ultrasound (ultrasonic horn; power dissipation higher than 60 W) has no particles with a size of greater than 20 μm as per the distribution patterns shown in Figures 8 and 9.…”