Lactose incompatibilities

Eyjolfsson R. Lisinopril-lactose incompatibility. Drug Dev Ind Pharm 1998 24 797-798. 

Compressed tablets that are composed of several layers require specially adapted presses designed with several fed hoppers. For a two-layer tablet, one granulation is first fed to a die and partially compressed into a soft tablet. The second granulation is added, and the total die components then are compressed fiiUy. Such procedures are used when the tablet ingredients may be incompatible, which requires separate granulations. If needed, a layer of inert ingredient, eg, lactose, is inserted between the two. 

The reaction of neomycin with many compounds has been described in Section 3, hence numerous reports of neomycin incompatibility may be expected. Dale and Rundman have extensively reviewed the compatibility of neomycin with substances that may be encountered by the formulation pharmacist. Kudalker et al 03 have described the incompatibility of the antibiotic with rancid oils, and the incompatibility with bentonite, a montomorill-onite clay, has been reported by Danti and Guth306. The incompatibility with lactose, causing a discoloration of the mixture has been studied by Hammouda and Salakawy- 0 . The amount of browning produced was shown to be dependant on the initial pH of the solution. The rate of discoloration of the lactose/neomycin powder was directly related to the temperature of storage and the relative humidity of the atmosphere. Discoloration was overcome by addition of sodium bisulphite. 

The API haloperidol was found to be incompatible with 5-(hydroxy-methyl)-2-furfuraldehyde, an impurity (resulting from degradation of lactose) in anhydrous lactose, and an adduct transformation product is formed (Fig. 24) (42). 

Because there is such a wide selection available, rational choice of the necessary excipients and their concentration is required. Consideration must also be given to cost, reliability, availability, and international acceptability. Although generally considered inert, formulation incompatibility of excipients is also necessary. Lactose, for example, can react with primary and secondary amines via its aldehyde group by Maillaird condensation reaction [6], and calcium carbonate is incompatible with acids due to acid-base chemical reaction and with tetracyclines due to complexation. Additionally, excipients can contribute to the instability of the active substance through moisture distribution. 

Incompatibilities poorly compatible with citric acid and saccharose solutions. Incompatible with ascorbic acid, gelatin, glucose, lactose, oxidizing agents, and saturated sodium bicarbonate solution. 

Lactose anhydrous is incompatible with strong oxidizers. When mixtures containing a hydrophobic leukotriene antagonist and anhydrous lactose or lactose monohydrate were stored for six weeks at 40°C and 75% RH, the mixture containing anhydrous lactose showed greater moisture uptake and drug degrada-... 

Lactose is also incompatible with amino acids, aminophyl-line, amfetamines, and lisinopril. ... 

FIGURE 9.10 HSDSC traces for 1 1 mixtures of aspiring with lactose (top) and magnesium stearate (bottom) following a step-isothermal temperature program. Aspirin/lactose shows no apparent incompatibility whereas aspirin/magnesium stearate shows a considerable heat response. (Wissing, 2000, unpublished data.)... 

As expected, there is clear evidence of incompatibility between the amine hydrochloride and the spray-dried lactose. However, the results also showed that moisture was the catalyst for decomposition, as no degradation was observed in the dry state even after 12 weeks storage at 90°C. At the time of this writing, Serrajuddin et al. (1999) have devised a protocol for compatibility testing (Table 6.19). 

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