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文献报告. 秦亚楠 20121125. 参考文献. Influence of Ultrasound on the Nucleation of Polymorphs of p - Aminobenzoic Acid Sandra Gracin, Marketta Uusi-Penttila, and Åke C. Rasmuson* Department of Chemical Engineering and Technology, Royal Institute of Technology, S-10044 Stockholm, Sweden

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Influence of Ultrasound on the Nucleation of Polymorphs of


Sandra Gracin, Marketta Uusi-Penttila, and Åke C. Rasmuson*

Department of Chemical Engineering and Technology,

Royal Institute of Technology, S-10044 Stockholm, Sweden

Received February 12, 2005; Revised Manuscript Received May 24, 2005















P =({dT}/{dt})mcp

the duration of each pulse, Δtson

I =P/A


the pulse repetition period, PRP

overall sonication

exposure (OSE),

the percentage of

Maximum intensity

(% MI)


Teq= 40, 38, 36,32, 30, and 20 °C

constant cooling rate of 1 °C/min,

one without sonication and the other applying sonication

sonication scheme (1/9-80)

started as the cooling began and was

stopped after nucleation had occurred


Eight series of induction time experiments were performed

to examine how the intensity of sonication, the temperature, and the supersaturation level influence induction time and the polymorphic form that crystallizes






the temperature Tson, chosen with respect to the desired supersaturationand always at least a few degrees above the expected metastable zone limit


Nucleation Temperature






20⁰C,α +β;其余


α +β


Induction Time

  • only the β –form appears
  • The shortest induction time was 6 minutes,corresponding to the highest average ultrasound Intensity
  • the induction time without ultrasound is 25-360 min for the α -form and 240-1140 min for the β-form at the same temperature
  • and supersaturation
  • the induction time quite clearly decreases with increasing average sonication intensity
  • the supersaturation is higher than in series 1-3, and the measured induction times were much shorter
  • crystallized form is always α.
  • the β-form is obtained at lower supersaturation and the α-form is obtained at higher supersaturation
  • the induction time decreases as the average intensity increases


  • In series 5, the induction time decreases quite strongly with increasing average sonication intensity from 25 to 2.5 min.
  • the polymorphic form that crystallizes shifts from the β-form at lower intensity to the α-form at higher intensity
  • in series 6 the induction time is longer and less dependent on the sonication intensity
  • In series 6 the crystallized form is always β


  • In series 7, the induction times are fairly long but clearly decrease with increasing average sonication intensity.
  • in series 7, β-formis obtained.
  • at moderate supersaturation, the sonication leads to that the β-form can be produced even above the transition temperature
  • in series 8, at low intensity, the β-form is obtained, and at high intensity, the α-form is produced
  • The threshold supersaturation for production of the β-form, tends to decrease with increasing temperature.


  • Ultrasonic treatment at all levels of intensity of the present work significantly shortens the induction time for nucleation of both polymorphic forms
  • the induction time in general decreases with increasing ultrasound intensity, that the influence of ultrasound is more pronounced at low supersaturation, and that the detailed format of the supply of the ultrasonic energy is less important
  • sonication clearly favors the formation of the β-form
  • When the supersaturation is close to the threshold, the intensity of the applied ultrasound may influence the polymorphic form that crystallizes, and in these cases a lower intensity promotes the appearance of the β-form


  • Depending on the solvent, it is well-known that carboxylic acids tend to form centrosymmetricdimers in solution
  • We believe that the kinetic preference for formation of the α-polymorph even below the transition temperature is due to the presence in the solution of such centrosymmetricdimer precursors
  • In dilute benzoic acid solutions, higher pressures and higher temperatures weaken the hydrogen bonds of the dimers and hence favor the dissociation of the hydrogen-bonded carboxylic acid dimers
  • In addition, there are several studies on the influence of ultrasound on acetic acid dimerization, where it has been found that the absorbed ultrasonic energy generates a shift in the dimer-monomer distribution in favor of the chain complex dimers and free monomers according to the scheme presented in Figure 8


  • We assume that the same may apply to PABA. Hence, an interesting possible explanation to that fact that sonication preferentially promotes the crystallization of the β-form is that sonication reduces the centrosymmetriccarboxylic acid dimerization in solution, possibly as a result of the high pressure and temperatures at the collapse of the cavities in accordance with the hot spot theory.
  • Another interesting aspect is the report that polarized laser light promotes the crystallization of the thermodynamically more stable but kinetically less favorableγ-polymorph of glycine.
  • The γ -polymorph structure consists of helical chains of roughly parallelhead-to-tail glycine molecules. Without polarized laser light the γ -polymorph of glycine whose structure consists of hydrogen-bonded double layers, whose basic unit is a hydrogen-bonded dimer (two antiparallel glycine molecules) will nucleate


  • It is suggested that the influence of the polarized laser light is due to partial alignment of solute molecules because of an interaction between the solute molecules and the laser-induced electric field.
  • In addition, it has been found that gas-phase samples of PABA that are subjected to laser radiation show the disruption of centrosymmetric hydrogen-bonded Dimers
  • On the other hand, there are significant electrical field gradients during the collapse of a bubble, and these are strong enough to cause bond breakage and chemical activity.
  • Hence, the preferential crystallization of the β-polymorph of PABA can perhaps also be explained as being the result of the disruption of PABA dimers by the ultrasound-induced electric field.


  • In the present study, it is shown that sonication significantly reduces the induction time for nucleation of PABA crystallized in aqueous solutions.
  • In addition, it is shown that sonication changes the relationship between the nucleation kinetics of the α-form and the β-form in favor of the latter.
  • Below the transition temperature at 25 °C, the crystallization of the β -polymorph becomes faster and more reproducible when ultrasound is applied.
  • The induction time decreases with increasing sonication intensity
  • By application of ultrasound, the β –polymorph can also be crystallized above the transition temperature, as long as the supersaturation is not too high.
  • Close to the critical supersaturation threshold, there is a threshold in sonication intensity, above which pure β -form is not obtained.
  • Overall there is an influence of the sonication average intensity, but there is no evidence that the more detailed format by which the ultrasound energy is supplied has an influence.


  • There are several reports in the literature showing that sonication may reduce the induction time for nucleation. However, to our knowledge this is the first time in solution crystallization that it has been shown that ultrasound may have an influence such that one polymorph in particular is promoted.
  • Our hypothesis is that this effect is due to an influence on the solute structuring in the solutions the clustering that precedes the nucleation of the two polymorphs. The α-form structure is based on centrosymmetriccarboxylic acid dimers. It is believed that the tendency to form dimers in the solution explains why there is a strong preference for the formation of the α-polymorph in an ordinary crystallization.
  • When ultrasound is applied, it is known from the literature that this dimerization tends to decrease, and it is our hypothesis that this is the explanation for the increased opportunity for the β-form to appear when the crystallizing solution is exposed to ultrasound.