Reduced sugar formulations

The Maillard reaction is likely to take on additional significance with the introduction of many new protein and peptide pharmaceuticals. For example, Tarelli et al. have demonstrated that lysine vasopressin undergoes rapid glycation in the presence of reducing sugars in both aqueous and solid formulations and that the N-terminal adduct can form rapidly even at — 20°C [52], A textbook that deals with the consequences for the chemical and life sciences of the Maillard reaction has been published [53]. 

A lesser-known degradation reaction of amines is the propensity to undergo formylation upon extended storage in formulations with carbohydrates, especially reducing sugars such as lactose. This has been described by Wirth et al. (40a) in a study of the reaction of fluoxetine hydrochloride with lactose (Fig. 44). 

Shalaev et al. (37) examined the influence of citric acid on the acid-catalyzed inversion of sucrose in the freeze-dried solid state. Even with less than 0.1% residual moisture, the colyophilization of sucrose with acidic substances can produce reducing sugars capable of further reaction with other formulation components that are susceptible to such reactions. 

Extract ability. About 60 to 70% of the total modifier added is extractable from resins cured under basic conditions and modified with alditols and methyl glycosides (2). In contrast, only about 0 to 20% of the xylose and prehydrolysate is extractable from samples of cured resin modified with 0.6 moles of either modifier per mole of phenol. Approximately 20 to 30% of xylitol (II), methyl xyloside (III), or glucose (IV) is extractable from neutral resins modified with these carbohydrates, indicating that neutral resins incorporate the carbohydrate more effectively than resins formulated and cured under basic conditions. In addition, free reducing sugars can be used directly. 

One of the most known formulation reaction in the pharmaceutical industry is the reaction between an amine (primary or secondary) and a carbohydrate (e.g., sugar) is known as the Maillard reaction (the browning reaction due to mixing of a reduced sugar and an amine) [13]. One of the examples of the Maillard reaction is fluoxetine HCl [14] Figure A15-6. The details of how to avoid this reaction in the formulation is outlined in Section 15.5 [Impact of excipients on Degradation products of API(s)]. 

Glycation has been observed in a lyophilized formulation of relaxin in which a glucose adduct was identified.Formulation of recombinant human DNase with lactose in a spray-dried state resulted in the addition of lactose molecules to five of the six Lys in the protein.A similar reaction was observed in a lyophilized formulation of hGH in lactose. Because of the tendency of reducing sugars to undergo the Maillard reaction with proteins, they are not the carbohydrates of choice for use in formulations. 

Sugars and polyols have often been used in formulations as well, particularly those that are in solid state. Commonly used carbohydrates include mannitol, sucrose, and trehalose. As previously described, the formulation scientist is strongly advised to steer clear of incorporation of reducing sugars (e.g., glucose and lactose) in formulations to avoid glycation and browning of the solution. 

As indicated previously, primary and secondary amines can also react with carbonyl compounds to form a mixture of compounds containing small molecules and polymers. The small molecule compounds obtained from an aldose and an amine have the common name Amadori products because the Amadori rearrangement is involved in their formation. The compounds generated from ketoses and amines are known as Heyns products (although the differentiation Amadori/Heyns is not always considered). The mechanism for the reaction of primary amines with a reducing sugar can be formulated as follows ... 

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