Influence of Ultrasound on the Nucleation of Polymorphs of p-Aminobenzoic Acid

Abstract

p-Aminobenzoic acid crystallizes in two different polymorphic forms: the α-form and the β-form. The α-form crystals are needle-shaped, while the β-form crystals have a more favorable prismatic shape. The system is enantiotropic with the transition temperature at approximately 25 °C. Below the transition temperature, the β-form is the thermodynamically stable polymorph but can only be produced at very slow supersaturation generation either in water or in ethyl acetate. In the present work, the influence of ultrasound on the nucleation of p-aminobenzoic acid polymorphs has been investigated by use of several different sonication intensities and schemes. It is shown that sonication significantly reduces the induction time for nucleation. By using controlled sonication, we were able to more reproducibly crystallize the β-form at more reasonable cooling rates. In addition, sonication is found to quite selectively favor the appearance of the β-polymorph. It is even possible to produce the pure β-form above the transition temperature where it is the metastable form and impossible to produce without sonication. The α-form structure is based on centro symmetric dimers formed by the association of carboxylic acid groups, while the β-form contains four-membered hydrogen-bonded rings of alternating amino and carboxylic acid groups. It is suggested that ultrasound disturbs the building up of the dimers in the solution and thus favors the crystallization of the β-polymorph.

The Effect of Ultrasound on the Crystallisation of Paracetamol in the Presence of Structurally Similar Impurities

“…Ultrasound can promote nucleation and generate substantial numbers of secondary nuclei from existing parent crystals in the reactors. This is consistent with previous work [19,26,27,47] undertaken at different frequencies by different researchers. Although different frequencies have been employed and the intensity of cavitation is likely to have varied significantly between studies the research consistently shows that nucleation may be triggered at lower supersaturation levels and the nucleation rate may be increased with the use of ultrasound.…”

“…Ultrasound can also influence crystal growth [20,25,26,36,40,[44][45][46] although the effect on crystal growth is not as dramatic as on nucleation and arises largely from enhanced mass transfer [46] and can influence crystal morphology. Other reported outcomes of ultrasonic intervention include influencing; which polymorph nucleates [23,47,48], crystal structure [30], crystal properties [49] and reaction crystallisation [45]. Several proposed mechanisms of the effect of ultrasound on crystallisation have been published.…”

“…These include the formation of local hot spots which arise from the large energy release on the collapse of cavitation bubbles creating highly localised regions of extremely high temperature and pressure [50,51], or due to rapid cooling which follows; shockwaves released from cavitation bubbles [52,53], promoting mass transfer and collisions between crystals and adjacent surfaces [54]. These effects of ultrasound on crystallisation have been demonstrated on pharmaceuticals and commodity chemicals including; lactose [35,39,42,55], alpha-dextrose monohydrate [20], glycine [48], p-aminobenzoic acid [47], adipic acid [28], benzoic acid [31], acetylsalicylic acid [27], protein [19] various food products [30,56,57] and in the crystallisation of inorganic materials such as potassium sulphate [26], potassium dihydrogen phosphate [32] and calcite [34]. Ultrasound has also been utilized in continuous crystallisation [28,[58][59][60].…”

Investigation of primary nucleation phenomena of acetylsalicylic acid crystals induced by ultrasonic irradiation—ultrasonic energy needed to activate primary nucleation

“…These effects bring considerable benefits to crystallization processes and the characterization of crystalline product, such as induction of primary nucleation [1][2][3][4][5][6][7][8][9][10][11][12], inhibition of agglomeration [13], reduction of crystal size [1,[4][5][6]14,15], manipulation of crystal size distribution [1,4,6,14], and modification of polymorphism [16]. Since primary nucleation can be induced by ultrasonic irradiation, it follows that this will allow control over the number of primary nuclei.…”

Effect of ultrasonic irradiation on the selective polymorph control in sulfamerazine

“…Moreover, sonication initiates primary nucleation, decreases metastable zone width, shortens induction time, and increases nucleation rate (Miyasaka et al, 2006a,b;Lyczko et al, 2002;Kim et al, 2002;Li et al, 2003;Amara et al, 2001;Thompson and Doraiswamy, 2000). Sonication can therefore be used to induce nucleation in systems where such a process is difficult to achieve, as well as to produce a more uniform particle size distribution and a smaller mean particle size (Gracin et al, 2005).…”