The influence of solvent composition on crystal agglomeration of paracetamol

Abstract: This thesis deals with the influence of solvent compositionon crystal agglomeration of paracetamol. Much work has beendone on characterisation of the crystalline product.Interfacial energies have also been determined for large singlegrown crystals. Isothermal desupersaturation batchcrystallization experiments have been performed using ninedifferent solvent compositions. The particles produced indifferent solvent compositions differ not only in particle sizedistribution, but also in content of single crystals andagglomerates. Furthermore, the crystal shape and size and thenumber of crystals in the agglomerates vary. Sieving, particleimage analysis and processing of measured image descriptorswith PCA (Principal Component Analysis) have been used toquantify the characteristic difference of particles produced indifferent solvent compositions. In addition, the agglomeratestrength, determined by crushing of single agglomerates,differs depending on in which solvent composition theagglomerates have been produced. A high content of acetonefavours crystal agglomeration and formation of agglomerateswith high strength. Crystallization in ethylene glycol,isopropanol, acetic acid or solvent mixtures with high contentof water give a particle product containing not onlyagglomerates but also an important fraction of single crystals.Furthermore, agglomerates produced in these solventcompositions exhibit significantly lower agglomerate strengththan agglomerates produced in solvent compositions with highcontent of acetone. The crystal surface tension has beendetermined from contact angle measurements. A surface tensionof 54 mJ/m2 was obtained for the largest crystal face {011}grown in aqueous solution. A strong negative polar contributionto the crystal surface tension indicates that the surface iselectron donating. The crystal surface tension has been used toestimate interfacial and interaction energies. There is arelationship between the influence of solvent composition onagglomeration observed on a macroscopic level and theinteraction at the solid-liquid interface on a molecular level.This relationship seems possible to capture by correlation ofobserved product characteristics to solvent polarity and to thedetermined interaction energies.Keywords:paracetamol, solvent composition,agglomeration, image analysis, principal component analysis,agglomerate strength, interfacial energy