Avvaru Seshasayana is a formulation group leader at Dr Reddy's Laboratories Ltd (India).

Avvaru Seshasayana

For an alternative view on combination drugs, go to 

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 approvals

  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.  

Stability problems in combination products can be attributed to three types of 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,

  which could lead to a number of possible adverse events.

: 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.

 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.

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. 

Preformulation and forced degradation studies

These studies attempt to diagnose the possible interaction between drugs, or drugs and excipients that might result in the loss in assay for one or more drugs, or generate impurities. Various combination products of tubercular drugs are pertinent examples of drug–drug, as well as drug–excipient interaction. For example, combination products of rifampicin and isoniazid form isonicotinyl hydrazone (HYD) as a result of the interaction of the imine group of rifampicin and the amino group of isoniazid. While this reaction is slow in a solid state, it increases exponentially in the presence of acid and other tubercular drugs, such as ethambutol hydrochloride and pyrazinamide.

  The interaction between rifampicin and isoniazid came to light after a pharmacokinetic study of rifampicin in combination products — the gastric acid led to a significant degradation of rifampicin, resulting in a 32% reduction in bioavailability.

  Preformulation studies and a forced degradation study can detect such interactions much earlier. 

Once the interacting component and interaction mechanism is known, a dosage form should be designed that addresses the incompatibility interactions. Several techniques have been proven to give a stable formulation, most of which are based on the principle of physical separation. Major techniques include microencapsulation of drugs prior to its incorporation, multilayered tablets with incompatible drugs added to different layers, and capsule dosage forms with different types of pellets or tablets containing different drugs.  

Combination products of telmisartan and hydrochlorothiazide are available as bilayered tablets with one layer containing telmisartan and a second layer containing hydrochlorothiazide. As telmisartan needs an alkaline ingredient for faster dissolution, meglumine is added to the telmisartan composition. Hydrochlorothiazide, however, is unstable in an alkaline condition, implying a monolithic tablet may be an unsuitable formulation. A bilayered tablet formulation containing two drugs in separate layers helps to minimize the degradation.

The same technique has also been suggested for combination products of telmisartan-amlodpine

  Lotrel is another combination product that contains two incompatible drugs — amlodipine and benazepril — in a capsule dosage form that contains a film-coated benazepril tablet and an amlodipine powder blend.

Coating one or more actives before incorporating them in a dosage form has been another successful technique. Coating can be in the form of microencapsulation, normal film coating or delayed release coating. Delayed release coating offers the additional advantage of releasing the coated drug over extended distances, thus avoiding potential 

 chemical interactions between the constituent drugs of a combination product. A capsule product containing a gastroretentive modified release rifampicin tablet and an enteric-coated isoniazide tablet, for example, has demonstrated reduced isoniazid-induced degradation of rifamipicin in acidic media and thus improved rifampicin bioavailability in a study.

Coating of incompatible drugs can also be used to prepare monolithic tablets of incompatible drugs as demonstrated by Wang 

  who developed a stable combination product of aspirin and ranitidine hydrochloride by compressing individually coated granules of the two actives.  

The above strategies can reduce initial incompatibility interactions, but such interactions may occur in the long-term because of the drug product's prolonged exposure to environmental factors (e.g., moisture, radiation, oxygen or temperature). Product packaging is crucial to mitigating such long-term risks; for example, hydrolysis of aspirin generates salicylic acid and acetic acid, which in turn leads to further degradation of other actives. Similarly, a combination of metronidazole, tetracycline hydrochloride and famotidine was found to be stable in a dry state, but unstable at higher humidity and temperature.

  Packaging such combination products using a moisture barrier pack, such as individual blister packing, might enhance product shelf-life. Packaging materials such as Aclar, aluminium foils, and bottles (cyclic olefin copolymers or high density polyethylene) have been demonstrated to offer an effective moisture barrier.

Preclinical studies and product specification

A judicious mix of formulation strategy and packaging design can significantly control drug degradation and improve product stability. Degradation leading to the generation of new degradants or known degradants in concentrations higher than the compendial specification, or innovator product impurity profile or ICH-specified limits is, however, still possible.

  The challenge is then to devise a product specification that offers sufficient shelf-life to the product without compromising its safety and efficacy.  

While product efficacy can be ensured through clinical trials, and accelerated stability results can project drug content at the end of shelf-life period, a safety assessment can be conducted by a battery of tests that include a single dose/acute dose toxicity, repeated dose 14–90-day duration general toxicity study with the actives and degradants, and genotoxicity studies (AMES test and chromosomal aberration test) with any new impurity.

  As recommended in ICH quality guidelines,

  these studies provide an opportunity to evaluate the safety of such degradants and thus qualify them.  

Qualification studies are necessary to justify the inclusion of new impurities or higher than the compendium-specified limit of known impurities. Yet, in certain instances the qualification may not be required; for example, if the impurity is a metabolite, or the absolute quantity as mentioned in the shelflife specification is not higher than the maximum absolute quantity in the market formulation or clinical trial product, the impurity will stand qualified. 

Incompatibility problems in fixed drug combination products can be overcome by a carefully designed development plan that detects such issues early in development. To increase the chances of producing a stable combination drug, researchers and manufacturers should rationally select the appropriate dosage form, composition and packaging, and evaluate the impact of incompatible interaction by conducting suitable preclinical studies. This will allow manufacturers and patients to reap the efficacy and compliance benefits that combination therapeutics have to offer.  

is Project Manager at Dr Reddy's Laboratories Ltd (India). 

is a formulation group leader at Dr Reddy's Laboratories Ltd (India). 

Reddy is an analytical group leader at Dr Reddy's Laboratories Ltd (India). 

is Senior Director at Dr Reddy's Laboratories Ltd (India). 

Drug Discovery Today: Therapeutic Strategies

., United States Patent Application (20080113023). 

W. Eisenreich, United States Patent Application (20060110450). 

A. Kohlrausch, United States Patent Application (20060078615). 

Articles

Combining drugs with synergistic mechanisms of action yields some indisputable benefits; improved efficacy, reduced dosing, enhanced patient compliance, to name just a few.