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Anomeric composition and solid state properties of lactose

University of British Columbia

Lactose is a widely used excipient in capsules and tablets. It has two anomeric forms, ⍺ (usually a monohydrate) and β (anhydrous). Lactose NF XVI is usually ⍺-lactose monohydrate. Physical properties, such as thermal behavior, x-ray diffraction characteristics, and true density of the anomers are different and not clearly understood. Pure samples of each anomer are difficult to prepare and all commercial lactose samples, especially the directly compressible grades, contain a certain amount of each anomer. It is not clearly established in what physical form the two anomers are present in a commercial sample. The physical form, and also certain differences in the physical properties, may depend upon the anomeric composition. An accurate and rapid gas chromatographic (GC) method for the determination of anomeric composition was developed. It involved derivatization of the lactose samples using trimethylsilylimidazole (TSIM). A mixture of TSIM in dimethylsulfoxide (DMSO) and pyridine (PYR) was used. DMSO dissolved the samples and PYR stabilized the solutions by preventing a phase separation which occurred if only TSIM and DMSO were used. Alpha-rich samples were dissolved directly into the mixture. Beta-rich samples were first dissolved in DMSO and then derivatized using a mixture of TSIM and PYR. An OV-225 column with helium as carrier gas was used for separating the anomers. The relative response of the anomers at a flame ionization detector was equal. Thus, the relative anomeric peak areas could be used as relative anomeric amounts. This avoided the use of an internal standard. The anomeric composition of a number of lactose samples was determined and was found to vary from 1.9 to 98.4% ⍺. A study of the thermal behavior of commercial lactose samples using differential scanning calorimetry and thermal microscopy showed that all ⍺-lactose monohydrate rich samples exhibited a dehydration peak followed by a melting peak when heated in an open pan. In sealed pans, the dehydration peak split into two components because of an overlap of an exotherm (due to dissolution of anhydrous lactose in the liquid water formed in the sealed pan, and recrystallization of β-lactose from the solution) with the endothermic dehydration peak. The extent of the split varied with the heating rate (which controls the extent of dissolution). Two new peaks, an endotherm and an exotherm, also appeared after the dehydration peak. The endotherm is due to anomeric conversion (determined using the GC method) rather than melting, and the exotherm is due to recrystallization into a new crystal lattice as the sample became β-rich. Since β-rich samples normally have a higher melting point than ⍺-rich samples, the melting peak shifted to a higher temperature when sealed pans were used. An unstable anhydrous a-lactose sample also showed the endotherm (anomeric conversion) and the exotherm (recrystallization of the β-rich form). On the basis of their powder x-ray diffraction patterns, the lactose samples can be classified into three types: 1. ⍺-lactose monohydrate rich, 2. β-rich, and, 3. samples showing peaks of both ⍺-lactose monohydrate and β-lactose. It was shown using quantitative x-ray diffraction that samples did not contain their anomeric impurity as a simple physical mixture. The true density of the lactose samples also varied with their anomeric composition. Beta-rich samples had greater true density than a-rich samples. This can be attributed to: 1. a simple physical mixture of ⍺-lactose monohydrate and β-lactose crystals, 2. a continuous substitutional solid solution, 3. an interstitial solid solution, or, 4. a mixture of two solid solutions. The first possibility was ruled out using quantitative x-ray diffraction because the relative anomeric x-ray peak intensities did not match the anomeric composition determined by GC. The second possibility was ruled out because there was no gradual shift of peaks in the x-ray diffraction patterns with the anomeric composition. The formation of an interstitial solid solution was not possible because this occurs only if the solute and solvent have very different molecular sizes. The quantitative x-ray diffraction experiments suggest that most samples contain a mixture of two solid solutions. Sorbed-moisture and surface area are important factors in tabletting. Various commercial lactose samples had specific surface areas ranging from 0.108 to 0.574 m²/g- Moisture-desorption and sorption were found to depend more on the relative crystallinities of the samples than on their surface areas.

Text

2010-08-28

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http://hdl.handle.net/2429/27872

Pharmaceutical Sciences

University of British Columbia

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