Antisolvent Crystallization of Telmisartan Using Stainless-Steel Micromixing Membrane Contactors

Abstract

Controlled continuous crystallization of the active pharmaceutical ingredient (API) telmisartan (TEL) has been conducted from TEL/DMSO solutions by antisolvent crystallization in deionized water using membrane micromixing contactors. The purpose of this work was to test stainless-steel membranes with ordered 10 μm pores spaced at 200 μm in a stirred-cell (batch, LDC-1) and crossflow (continuous, AXF-1) system for TEL formation. By controlling the feed flow rate of the API and solvent, through the membrane pores as well as the antisolvent flow, it was possible to tightly control the micromixing and with that to control the crystal nucleation and growth. Batch crystallization without the membrane resulted in an inhomogeneous crystallization process, giving a mixture of crystalline and amorphous TEL materials. The rate of crystallization was controlled with a higher DMSO content (4:1 DMSO/DI water), resulting in slower crystallization of the TEL material. Both membrane setups, stirred batch and the crossflow, yielded the amorphous TEL particles when deionized water was used, while a crystalline material was produced when a mixture of DI water and DMSO was used.

Investigation of the Influence of Anti-Solvent Precipitation Parameters on the Physical Stability of Amorphous Solids

“…In addition, the type of anti-solvent also affects the preparation of the amorphous solids. For instance, the use of deionized water as the anti-solvent resulted in the formation of amorphous telmisartan particles, whereas the use of a mixture of deionized water and dimethyl sulfoxide (DMSO) as the anti-solvent led to the production of the crystalline form [ 9 ]. In addition, the feeding rate of the anti-solvent also has an impact on the preparation of amorphous solids; for example, using a higher feeding rate of the anti-solvent results in increased supersaturation, therefore obtaining the amorphous form of disodium guanosine 5′-monophosphate, while the formation of hydrate crystals occurred at a slower feeding rate of the anti-solvent [ 10 ].…”

Molecular Insights from Spectral and Computational Studies on Crystalline and Amorphous Telmisartan

“…TEL (Figure ), characterized by high permeability and pH-dependent low aqueous solubility (0.09 μg/mL), belongs to the BCS class II drug category, with a dissolution rate-limited oral bioavailability of 40–58% . TEL is considered as a high glass forming molecule with a moderate glass stability and several strategies like use of polymers in conjunction with alkalizers, , antisolvent crystallization, development of cocrystals, − and coamorphous systems have been investigated to inhibit recrystallization of amorphous TEL (AM-TEL) to maximize its solubility and dissolution profile. Most recently, Bennett et al and Sharma et al .…”