Lactose crystalline forms

Both maltose and lactose, being reducing sugars, give osazones which differ from one another and from glucosazone in crystalline form. Sucrose (G-r-r-F), having no potential aldehyde or ketone grouping, does not form an osazone. 

X-ray diffraction studies are usually carried out at room temperature under ambient conditions. It is possible, however, to perform variable-temperature XPD, wherein powder patterns are obtained while the sample is heated or cooled. Such studies are invaluable for identifying thermally induced or subambient phase transitions. Variable-temperature XPD was used to study the solid state properties of lactose [20], Fawcett et al. have developed an instrument that permits simultaneous XPD and differential scanning calorimetry on the same sample [21], The instrument was used to characterize a compound that was capable of existing in two polymorphic forms, whose melting points were 146°C (form II) and 150°C (form I). Form II was heated, and x-ray powder patterns were obtained at room temperature, at 145°C (form II had just started to melt), and at 148°C (Fig. 2 one characteristic peak each of form I and form II are identified). The x-ray pattern obtained at 148°C revealed melting of form II but partial recrystallization of form I. When the sample was cooled to 110°C and reheated to 146°C, only crystalline form I was observed. Through these experiments, the authors established that melting of form II was accompanied by recrystallization of form I. 

This particular trimethylglucose is unique in that it was separated in crystalline form from the hydrolyzates of the methyl ethers of several naturally-occurring glucose polymers almost two decades before it was synthesized from glucose. These natural sources, which still furnish the most convenient routes for the preparation of 2,3,6-trimethyl-D-glucose, include maltose,124-128 cellobiose,127,128 lactose,122-181 starch,71,182 glycogen,188,184 cellulose,185-187 and lichenin. 188,189 The literature pub-... 

Lactose may be obtained in two crystalline forms a-lactose and P-lactose (in addition to amorphous forms). The alpha form is obtained when water is incorporated into the lattice structure during crystallization (usually by supersaturation below 93.5°C) (5). Alternatively, the beta form does not contain water and exists as a non-hygroscopic and anhydrous form. Amorphous lactose is formed when either the crystallization is rapid or sufficient transient energy is introduced into the crystalline forms (74), i.e., spray drying (75), micronization and milling (76), freeze-drying, and anti-solvent crystallization (77). 

Some properties of a- and /1-lactose are summarized in Table 2.3. Mixed a// crystals, e.g. a5/ 3, can be formed under certain conditions. The relationship between the different crystalline forms of lactose is shown in Figure 2.8. 

Lactose normally occurs naturally in either of two crystalline forms— a-monohydrate and anhydrous /3—or as an amorphous glass mixture of a- and /3-lactose. Several other forms may be produced under special conditions. 

Lactose can occur in two crystalline forms, the a-hydrate and the P-anhydrous forms and can occur in an amorphous or glassy state. The most common form is the a-hydrate (C H On-HjO), which can be obtained by crystallization from a supersaturated solution below 93.5°C. When crystallization is carried out above 93.5°C, the crystals formed are of p-anhydrous type. Some properties of these forms have been listed by Jenness and Patton (1959) (Table 4-6). Under normal conditions the a-... 

Diluents for direct compression formulations are often subject to prior processing to improve flowability and compression, for example, amorphous lactose, but this can contribute to reduced stability especially under high-humidity conditions when reversion to the crystalline form is more likely [6]. 

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... 

Lactose exists in two isomeric forms a and p. It is possible to obtain the a-monhydrate, anhydrous crystalline a and p forms, as well as an amorphous form. Thepharmaceutical properties of these various types are different. The hardness of tablets obtained using amorphous lactose produced by lyophilization is 10 times that obtained using crystalline forms. During milling, it has been observed that the monohydrate loses part of its water of crystallization and of its crystallinity. Heat treatment of different lactoses has permitted the discovery of an anhydrous, unstable a form and a crystal containing a and p in the ratio 1 1. Under the influence of high degrees of humidity, amorphous lactose crystallizes and anhydrous forms tend to reconvert to the monohydrate. 

In 1855, Berthelot noticed that freshly prepared lactose solutions show a progressive fall in optical rotation with time. This phenomenon, which was soon confirmed," had previously been reported for D-glucose, and was later given the name mutaroiation Several crystalline forms of lac-... 

In the solid state, lactose appears as various isomeric forms, depending on the crystallization and drying conditions, i.e. a-lactose monohydrate, P-lactose anhydrous, and a-lactose anhydrous. The stable crystalline forms of lactose are a-lactose monohydrate, P-lactose anhydrous, and stable a-lactose anhydrous. 

A suspension of a-lactose monohydrate crystals in a lactose solution is atomized and dried in a spray drier. Approximately 10-20% of the total amount of lactose is in solution and the remaining 80-90% is present in the crystalline form. The spray-drying process predominantly produces spherical particles. The compactibility of the material and its flow characteristics are a function of the primary particle size of the lactose monohydrate and the amount of amorphous lactose. " ... 

Figure 8.6b shows sorption isotherms for dried skim milk, of which about 50% is lactose. The lactose can remain amorphous when the milk is spray-dried. It can also be made with crystalline lactose, and the normal crystalline form is a monohydrate. The water of crystallization is not available as a solvent, which means that aw is smaller than for amorphous sugar at the same water content, provided the latter is fairly small. At higher water content, the curves cross, and amorphous sugar may crystallize, taking up part of the water. 

Sweetened condensed milk is supersaturated with lactose, and the lactose crystals formed tend to settle and also give the product a sandy mouth feel. To prevent this, crystal size should be at most 8 pm, and one generally tries to achieve this by adding crystalline seed lactose, about 0.3 g per kg product. Calculate what the maximum size of the seed particles may be. One kg of sweetened condensed milk contains about 110 g lactose, 440 g sucrose, and 260 g water. Consult also Table 2.2. 

We will illustrate the phenomenon for the crystallization of lactose. Lactose is a reducing sugar, and in solution the a and p anomers are in equilibrium with each other the ratio p over a is about 1.6. The crystallization of a-lactose monohydrate, the most common crystalline form, has been studied in detail. Figure 15.10 depicts a crystal as formed at... 

Near infrared has been used to quantify amorphous content in a crystalline matrix [64], mixtures of multiple polymorphic forms [65], and physical mixtures of crystalline and amorphous drug in the presence of excipients [66,67]. Otsuka et al. [68] found that Fourier transform (FT)-NIR outperformed x-ray powder diffraction (XRPD) with respect to accuracy statistics over the calibration range and down to 1% (w/w). Other quantitative studies have reported prediction errors of 5 to 6% (w/w) of y-IMC (indomethacin) in a sample matrix including amorphous and a-IMC [69]. These results demonstrate NIR selectivity of the solid-state forms of IMC. Selectivity, the proportion of analyte signal unaffected by other spectral interferences, is especially critical for monitoring dispersions where physical instability could manifest in a combination of amorphous and crystalline forms (including various polymorphs). Similar studies were performed for lactose and showed the possibility to quantify down to 0.5% of crystalline material in an amorphous base [70]. 

The phenomenon of mutarotation for D-glucose had been recognized since 1846. Also as early as 1856, two different crystalline forms of lactose had been obtained. 

Lactosazone in crystalline form can only be obtained with difficulty from urine containing lactose. 

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