Crystalline isothermal microcalorimetry

Sebhatu, T. Angberg, M. Ahlneck, C. Assessment of the degree of disorder in crystalline solids by isothermal microcalorimetry. Int. J. Pharm. 1994,104, 135-144. 

Gustafsson et al. used SSNMR and isothermal microcalorimetry to investigate the amorphous component of lactose. In general, the detection limits for crystalline forms are much better than for amorphous forms due to the much broader resonances characteristic of disordered systems. The two techniques were found to be in agreement with each other in the characterization of the degree of disorder in the system. Completely amorphous lactose (prepared by spray drying) was mixed with completely crystalline lactose monohydrate... 

Briggner L-E, Buckton G, Bystrom K, Darcy P. Use of isothermal microcalorimetry in the study of changes in crystallinity induced during the processing or powders. Int J Pharm 1994 105 125-135. 

Microcalorimetry is an extremely sensitive technique that determines the heat emitted or adsorbed by a sample in a variety of processes. Microcalorimetry can be used to characterize pharmaceutical solids to obtain heats of solution, heats of crystallization, heats of reaction, heats of dilution, and heats of adsorption. Isothermal microcalorimetry has been used to investigate drug-excipient compatibility [82]. Pikal and co-workers have used isothermal microcalorimetry to investigate the enthalpy of relaxation in amorphous material [83]. Isothermal microcalorimetry is useful in determining even small amounts of amorphous content in a sample [84]. Solution calorimetry has also been used to quantitate the crystallinity of a sample [85]. Other aspects of isothermal microcalorimetry may be obtained from a review by Buckton [86]. 

Isothermal microcalorimetry is a versatile method that can be used for diverse applications such as assessing chemical stability, heats of dissolution by solution calorimetry, and binding affinities by titration calorimetry. An important application of isothermal microcalorimetry related to characterization of solids is the determination of the amorphous content [9]. Typically, it is desired that the product of a crystallization process is 100% crystalline. If the crystallization process is carried out in a nonoptimized way, the resulting solid may contain amorphous fractions. One possible cause for this could be that the crystallization is carried out too fast. Also, processes following the crystallization process, such as drying or milling, may induce formation of amorphous fractions. In most instances such amorphous fractions are undesired, since they may reduce the chemical stability and change the dissolution characteristics of the product. 

Studies of the desolvation of solvatomorphs can be conducted using VT-XRPD. For instance, after the dehydration of a hydrate phase, one may obtain either a crystalline anhydrate phase or an amorphous phase and the XRPD pattern will clearly indicate the difference. In addition, should one encounter an equivalence in powder patterns between the hydrate phase and its dehydrated form, this would indicate the existence of channel-type water (as opposed to lattice boimd water). In one study, the solid-state properties of the isomorphic desolvates of cephalexin, cefaclor, erythromycin A, and spirapril hydrochloride were investigated, with the hygroscopicity of the compounds being evaluated using a vacuum moisture balance and the structural relaxation measured using a combination of VT-XRPD and isothermal microcalorimetry. " ... 

Isothermal microcalorimetry has also been used to determine the crystallinity of mixtures of amorphous and crystalline antibiotics [63]. DSC could not be used for this process since the samples decomposed prior to melting and an accurate quantification of the heat of fusion could not be determined. In contrast to studies carried out by Hogan et al. [ 64 ], in this case, it was shown that the heat of solution was not dependent on residual water content. The importance of initial water content is greatest when dealing with hydratable ionic species, since sodium and quaternary ammonium salts have very high heats of hydration. Therefore, before performing any analysis one must care to identify the extent of residual solvents or water present, as well as their effects on the heats of solution in the chosen system. 

Isothermal microcalorimetry. The study of amorphous materials using microcalorimetry relies on the physical properties of the amorphous fraction being significantly different to the crystalline form. In general, amorphous materials tend to be hydrophilic and thermodynamically unstable. If maintained in a high RH environment, the amorphous material would eventually... 

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