The role of ultrasound in pharmaceutical production: sonocrystallization

Abstract

Objectives The main aim of this review was to develop a critical discussion of the key role ultrasound (US) can play on the production of active pharmaceutical ingredients (APIs) by discussing the versatile effect this type of energy produces. Methods The different crystallization techniques that can be assisted and improved by US are discussed in the light of the available US devices and the effect pursued by application of US energy. Simple and complex analytical methods to monitor API changes are also discussed. Key findings The countless achievements of API US-assisted production are summarized in a table, and outstanding effects such as narrower particle size distribution; decreased particle size, induction time, metastable zone and supersaturation levels; or a solubility increase are critically discussed. Conclusions The indisputable advantages of sonocrystallization over other ways of API production have been supported on multiple examples, and pending goals in this field (clarify the effect of US frequency on crystallization, know the mechanism of sonocrystallization, determine potential degradation owing to US energy, avoid calculation of the process yield by determining the concentration of the target drug remaining in the solution, etc.) should be achieved.

Agglomeration Control during Ultrasonic Crystallization of an Active Pharmaceutical Ingredient

“…In this stage, new crystalline material will be deposited on the surfaces of the priory formed crystals. This deposition preferentially takes place on damaged edges and surfaces, masking possible erosion effects caused by sonofragmentation [5,19,61]. Finally, ultrasound also increases the collision frequency by a direct interaction between shockwaves or liquid jets and the aggregates which will disrupt the latter before an agglomerative bond is formed [25].…”

“…The benefits of this technology for crystallization were demonstrated before and include reduced metastable zone width, narrow particle size distribution and homogeneous crystal morphology [5,[26][27][28]. Although the exact mechanism of these phenomena is not yet understood, the proposed hypotheses attribute this to acoustic cavitation, involving the formation and implosion of micron-sized bubbles, and its accompanying mechanical effects [29,30].…”

“…In addition, most research only targets the behavior of inorganic compounds or small organic substances [5,28,[35][36][37]. Although some active pharmaceutical ingredients were studied, more investigation is needed to evaluate the feasibility of sonication in pharmaceutical processes [5,27,38]. Therefore, this study aims to evaluate the potential of ultrasound for agglomeration control during the recrystallization of a commercially available API produced by Johnson & Johnson.…”

“…Prolonged operation of the ultrasonic source can also result in erosion of the probe which can subsequently contaminate the crystal suspension. In addition, most research only targets the behavior of inorganic compounds or small organic substances [5,28,[35][36][37]. Although some active pharmaceutical ingredients were studied, more investigation is needed to evaluate the feasibility of sonication in pharmaceutical processes [5,27,38].…”

“…On the other hand, these characteristics also provide the opportunity to control the drug release profile after intake into the human body. As a result, industrial processes exploit numerous particle engineering techniques in combination with crystallization to produce crystals that meet both the bioavailability and processing requirements [1][2][3][4][5][6].…”