Time-resolved studies of the crystallisation and dehydration of lactose and other hydrates using synchrotron x-ray and neutron powder diffraction techniques

Abstract

In-situ time-resolved synchrotro11 x-ray and neutron powder diffraction tC'c:hniques have bc(-'n applied to the study of solid stat<' structural t.ransi tions within the organic. polymor­phic molecular systems of lactose. trehalose and t heophylline. Diffraction techniques offer an unequalled 1ucthod of polymorph identification and q11antification. and have repeatedly demonstrated throughout this work that they can be utilised to follow. and kinetically eval­uate strnctural transitions in real t.ime.
The study of lactose crystallisation provides fmther proof of the transient ( lo::1/3) mixed crystal polymorpl1 as the initial crystallisation product. which is then followed by the typical beta lactose'. and alpha lactose monohydrate phases. The formation of the (lo:: l,B) mixed crystal form has been mapped. and kinetically analysed; the complex. multi-step crystallisa­tion behaviour is likely to result from the high degree of polymorphism which is displayed withi11 the lactose' syste111.
The dehydratio11 studies of the three systems show that dehydration kinetics can vary as a functiou of procet;sing conditious. and c'uviroumeuts. Evidence of a previously uudocumeuted theophylline polymorph has been observed. which is accessible via the 8eeded dehydration of theophylline monohydrate with anhydrous tlwophylline form II.
The pmest production of beta lactose from the 1-Jicnual dehydration of alpha lac Lose monohydrate to da.t<> is documented. and is attained from dehydration within a hydrophobic. cocoa butter environment: this transition is mediated via a crystalline phase whose identity is uncertain. yet displays a unique Bragg peak at rv 12.87° 20.
Neutrou diffractio11 techniques reveal that the water content. and crystalline weight frac­tion of trehalosc dihydrate arc decoupled quantities. and the dihydrate lattice can sustain substantial water loss. These observations provide supporting evidence of a. transiently stable. partially hydrated state of trehalose.
In addition. the applicability of the Dl9 single-crystal diffraction beamline at the In­stitut Laue-Langevin in the study of hydrated powder samples is reported. demonstrating the versatility of the instrument. with the capability of performing dynamic studies with a time-resolution of 15 s.