FUNDAMENTOS DE MÁQUINAS DE CONTROL NUMÉRICO

1.11.1 INTRODUCTION

Lactose is extensively used as a diluent in tablets and capsules for pharmaceutical formulations. It is a disaccharide composed of galactose and glucose, and consists of two isomeric forms a- and p-lactose, shown in Figure 1.13. Lactose has been identified with three crystalline forms: a-lactose monohydrate, a-anhydrate and P-anhydrate, and also an amorphous form (Otsuka et al 1991, 1993). The production of a- and p-lactose isomers is dependent on the temperature. If lactose is dissolved in water at a temperature below 93.5°C, then crystallisation of the a-lactose isomer takes place. However, if the temperature is above 93.5°C, then the P-lactose isomer crystallises from

the aqueous solution (Olano et al, 1983). There is also a difference in the way a- and p- lactose crystallise. When p-lactose is crystallised, no water is incorporated into its crystal lattice, and therefore p-lactose exists in an anhydrous form only. This is different from a-lactose, which can exist as a monohydrate and anhydrous crystalline forms (Lerk et al, 1984). CH,OH C H /)H a * iACtOS6 CM,OH CH,OH

p - lactose

Figure 1.13 Structural formula o f a- and f-lactose (Reproduced from Handbook o f Pharmaceutical Excipients, 1986)

1.11.2 PHARMACEUTICAL APPLICATIONS OF LACTOSE POWDERS

a-lactose monohydrate is the most common of the lactose powders and is mainly used for granulation formulations (Angberg, 1995). Anhydrous lactose powders, with different proportions of anhydrous a- and p-lactose, are mainly used as direct compression excipients (Angberg et al, 1991). Bolhuis et al (1995) found that anhydrous lactose is a suitable direct compression excipient for use in tabletting. Amorphous lactose can be formed by rapid drying of dissolved lactose from solution (as in spray-drying) or by mechanical activation (as in milling). Commercial spray-dried lactose is used as a direct compression excipient and consists of a mixture of a-lactose monohydrate and amorphous lactose. The amorphous lactose comes from the rapid drying of dissolved lactose during spray-drying (Sebhatu et al, 1994b). The amorphous portion of the commercial spray-dried lactose is responsible for the good qualities as a direct compression excipient, such as good binding and flow properties (Sebhatu et al,

1.11.3 THERMAL ANALYSIS OF LACTOSE

Thermal analysis of a-lactose monohydrate shows a water loss (dehydration) peak at ca. 145°C and a melting peak at ca. 220°C. A 5% weight loss is detected, usually between 100°C and 150°C, representing the loss of the crystal water and corresponding to the dehydration peak at ca. 145°C (Otsuka et al, 1991).

It is well known that various processes such as spray-drying (Elamin et al, 1995), freeze-drying (Berlin et al, 1971), and milling (Krycer and Hersey, 1981) lead to the production of amorphous lactose. The detection of amorphous lactose has been studied using microcalorimetry, which accurately measures the heat flow accompanying the amorphous to crystalline transition on exposure to water vapour. The measurements are carried out at conditions that favour crystallisation e.g. suitable RH and temperature (Sebhatu et al, 1994a). DSC (differential scanning calorimetry) and XRPD (X-ray powder diffraction) can also be used to detect amorphous material; however, the minimum amount of amorphous material that can be accurately detected is 10% (Angberg, 1995 and Saleki-Gerhardt et al, 1994). Bulk analytical techniques such as DSC and XRPD are unable to accurately detect the small amounts of amorphous material (< 10%) that is produced at the surface of the particle as a result of processing. However, since the amorphous regions of the solid preferentially absorb water over the crystalline regions, microcalorimetry is able to detect even small amounts of amorphous material through its use of water vapour sorption to induce crystallisation of the amorphous regions (Elamin et al, 1995 and Angberg et al, 1995). Crystallisation of amorphous spray-dried lactose can lead to a mixture of a- and P-lactose (Sebhatu et al,

1994a and Briggner et al, 1994). p-lactose exists as a stable anhydrate and thermal analysis of P-lactose shows that a melting peak at about 230°C occurs, with no other thermal transitions occurring below this temperature (Berlin et al, 1971).

1.11.4 MUTAROTATION OF LACTOSE

Berlin et al (1971) found that there was no measurable water sorption by p-lactose below 97% RH. It was then concluded that P-lactose is completely non-hygroscopic below 97% RH. However, it was also found that above 97% RH, P-lactose sorbs sufficient moisture to form a concentrated solution and undergo mutarotation to a- lactose (Berlin et al, 1971). Angberg et al (1991) investigated the effect of water uptake on anhydrous lactose consisting of 31% a- and 69% P-lactose. It was found that the

incorporation of water in to the anhydrous a-lactose could be followed using microcalorimetry at 58% RH. When the anhydrous lactose was studied using microcalorimetry at 94% RH, it was found that as well as the incorporation of water, the anhydrous P-lactose mutarotates to anhydrous a-lactose with subsequent incorporation of hydrate water to form a-lactose monohydrate. Mutarotation was also found to occur at lower humidities up to 75% RH. At 75% RH, it was found using gas chromatography (GC) that mutarotation of p-lactose occurs to a more limited extent when compared to mutarotation at 94% RH. However, it was also found that the mutarotation occurs in parallel with the incorporation of water in to the original 31% anhydrous a-lactose. An explanation for this may be that certain regions in the powder have a higher water content despite the overall humidity being relatively low, thus allowing mutarotation to occur (Angberg, 1991). As described earlier, this could be due to the ‘amplification’ effect of water sorption by a material that is activated by processing to produce local regions of disorder.

Mutarotation of lactose may also occur during the heating of lactose. Olano et al (1983) found that mutarotation of a-lactose monohydrate proceeds below the melting point, and that unstable anhydrous a-lactose may be an intermediate in the transformation. Lerk et al (1984a) showed that unstable anhydrous a-lactose, formed when a-lactose monohydrate is heated under vacuum at 100-130°C, displayed an increase in the p- lactose content when heated to 180°C in the DSC. A significant increase in the p-lactose content was also noted for a-lactose monohydrate and stable anhydrous a-lactose, formed by desiccation over methanol, at a temperature of ca. 220°C (Lerk et al, 1984a). The relative humidity has been found to affect the mutarotation of lactose during heating (Olano et al, 1983). Olano et al (1983) found that in the absence of water vapour, lactose can be heated up to 170°C at 4°C/min without alteration of the initial isomeric composition of lactose. The maximum transformation occurred when the humidity used was 100% RH, leading to the presence of up to 95% p-lactose. The rate of mutarotation increased with temperature, and also depended on the crystalline form of lactose. Stable anhydrous a-lactose mutarotated at the slowest rate, and unstable anhydrous a-lactose and a-lactose monohydrate at the fastest rates.

1.11.5 SELECTION OF LACTOSE FOR DRYING INVESTIGATIONS

Lactose has been selected as a model substance for microwave-vacuum drying investigations since, as described above, during processes such as spray-drying, freeze- drying, and milling, crystalline lactose can be transformed in to the amorphous form. The detection of amorphous lactose, particularly small amounts due to processing, has been well established so that the effect of microwave-vacuum drying investigations can be easily detected.

1.12 MALTODEXTRINS