CONTRACT MANUFACTURING
The main challenge of all the different parenteral dosage forms is to achieve a good
compatibility of the drug substances with the excipients as well as the compatibility of the preparations with the primary container.
Parenteral preparations may require the use of excipients that should be biocompatible, be selected for the appropriate use and to be included at the minimum efficient concentration.3
The functionality of these excipients is as follows:
• To make the preparations isotonic with respect to blood (glucose/dextrose, mannitol, sodium chloride…)
• To adjust the pH to the physiological one (mineral or organic acids or salts)
• To prevent the degradation of the drug substances (stabilizer…)
• To ensure or increase the drug substance’s solubility
• To provide adequate antimicrobial preservative property (only applicable to multidose preparations)
It should be stressed that excipients should not adversely affect the intended medicinal action of the drug products, nor at the concentration used to cause toxicity or undue local irritation.
Challenges in Formulations
The main challenge of all the different parenteral dosage forms is to achieve a good compatibility of the drug substances with the excipients (no formation of new impurities either by degradation of the drug substance or formation of new chemical entity between the drug substance and the excipients) as well as the compatibility of the preparations with the primary container (no leachable or adsorption to container).3
With regards to solutions and emulsions, the drug substances should be soluble and remain soluble during the entire shelf-life of the drug products. When drug substances are not soluble, dissolution can be achieved by the use of co-solvents, surfactants, or a soluble pro-drug, or eventually the use of solubility
Pharmaceutical Outsourcing | 14 | November/December 2016
Figure 2. Decision tree for sterilization choices for non-aqueous liquid, semi-solid or dry powder products (CPMP/QWP/054/98)
enhancers such as cyclodextrins thanks to the formation of inclusion complex.
The pH is one of the critical aspects of parenteral preparations which should have a
pH close to the physiological one. However in certain cases, a compromise should be found between the pH ensuring stability of the drug substance (such for peptides requiring alkaline pH or proteins at pH close to the isoelectric point) and the physiological one. In all cases, large volume preparations (LVP, i.e. more than 100 ml as defined in pharmacopeia) should not contain a pH buffer as the blood has already a buffer effect property that could enter into competition with the injected drug product.
The stability of the drug substance is another critical point that a formulator can face during the development of the formulation. Unstable drug substances will lead to the formation of new impurities jeopardizing the safety of use of the preparations. When the use of a
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