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With declining numbers of new chemical entities (NCEs), there is a new-found aggression for developing differentiated products
using currently approved drugs. Fixed drug combination products have emerged as a differentiation strategy, as is evident
by the increasing number of such product approvals1 and recent launches. The strategy involves identifying molecules that, when combined, will lead to an improved therapeutic
outcome compared with other treatment options. The rationale for such products are the associated advantages, such as improved
patient compliance, complementary pharmacodynamic effect and improved bioavailability. Product stability, however, is a common
and significant factor affecting the outcome of the product development project.
What are the stability issues?
Stability problems in combination products can be attributed to three types of interaction:
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Drug–drug chemical interaction: two or more drugs interact directly, resulting in drug degradation and a number of impurities; for example, lisinopril combined
with aspirin undergoes acetylation to generate acetyl lisinopril,2 which could lead to a number of possible adverse events.
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Drug–excipient interaction: a drug in a combination product has an excipient that is incompatible with other drugs; for example, telmisartan in a telmisartan-hydrochlorothiazide
combination product needs the incorporation of an alkaline excipient. Hydrochlorothiazide, however, degrades in an alkaline
environment.3
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Drug–excipient–drug interaction: occasionally, combination drugs, which may not be interacting directly, exhibit incompatibility in the presence of certain
formulation components; for example, the combination of rifampicin and isoniazide is stable unless there is any excipient
or agent that creates an acidic or alkaline environment.4
The incompatibility interactions are often facilitated by the close contact between drugs and excipients. There are other
factors such as the pH of the formulation microenvironment, temperature and moisture — all of which initiate and catalyse
chemical reactions.
The instability of combination drugs is manifested in various forms that can be broadly classified into three groups: physical
instability, which includes changes in physical appearance (e.g., colour, precipitation, hardness, etc.); chemical instability
— variation in drug content and impurities; and functional instability — changes in the drug release pattern.
We can address incompatibility challenges
Significant research has been conducted to understand the root cause of drug incompatibility issues. The vast amount of literature
and knowledge on the structural and chemical properties of drugs and excipients can help development teams to assess possible
incompatibilities and make a development strategy that addresses such challenges effectively.
As previously mentioned, the instability of combination products is mainly the result of incompatibility between formulation
components; for example, drug and excipients. A systematic development strategy is the first step to detect any potential
compatibility issues and accordingly design the product. It is, therefore, possible, to safely develop a combination drug
product that is stable and has a sufficient shelf-life, so long as the following key factors are considered: preformulation
and degradation; dosage form selection; packaging development; preclinical studies; and product specification.
