How to Deal with Incompatibility Issues in Drug Formulations

Fixeddose combinations (FDCs), consisting of two or more active pharmaceutical ingredients (APIs), are commonly recommended by WHO and other health agencies in therapeutic areas such as common cold, tuberculosis, malaria, cardiovascular diseases, and several others. Formulating FDCs in a single oral dosage form is advocated especially for long-term therapies to reduce the number of dosing units and improve patient convenience, compliance, cost-effectiveness, and therapeutic outcomes.   

One of FDCs’ biggest challenges is the likelihood of drug-drug incompatibilities that may influence the product’s stability, bioavailability, or therapeutic efficacy. Commonly used formulation approaches to physically separate the interacting APIs and overcome these incompatibilities include multilayer tablets and combination fills in capsules.  

 

Multilayer tablets 

The incompatible APIs are incorporated in separate layers and compressed into a single tablet. A placebo layer is sometimes added between the drug layers to minimise interactions at the interface. Some examples where the multilayer tablet approach has been employed to overcome the incompatibility issues include:  

  1. Incorporation of anti-hypertensive drugs, losartan potassium, and amlodipine besilate in a single tablet results in gelation of losartan in the acidic environment of the stomach and subsequent trapping and retarded dissolution of amlodipine. Bilayer tablets have been designed to physically separate and independently release the two drugs.  
  2. Anti-tubercular drugs, rifampicin, and isoniazid are physically incompatible. Isoniazid induces polymorphic changes in rifampicin, enhances its degradation in an acidic stomach environment, and reduces its bioavailability. Bilayer tablets with an immediate-release layer containing rifampicin and a retarded-release layer containing isoniazid have been developed to avoid simultaneous release of both drugs in the stomach and prevent interaction. 
  3. Simvastatin (anti-hyperlipidemic) undergoes degradation in the alkaline environment necessary for the dissolution of telmisartan (anti-hypertensive), and this restricts their incorporation in a single monolithic tablet. A pH-dependent release of the two drugs from a bilayer tablet could overcome this incompatibility.

Combination fills in capsules 

A combination fill of multiparticulates, liquids, semisolids, powders, granules, tablets, or capsules can be adapted to physically separate and deliver incompatible FDCs in the same capsule. Following are the few examples of this approach reported in the literature: 

  1. Atenolol and enalapril form a eutectic mixture when compressed together into tablets. Individually granulated atenolol and enalapril, when combined in hard capsules, were found to be stable for over a year. 
  2. Rifampicin and isoniazid can be individually formulated as modified-release pellets and combined in capsules.  
  3. Co-encapsulation of bismuth subcitrate, metronidazole, tetracycline, and omeprazole, a combination therapy for Helicobacter pylori, produces a beige-coloured degradation product. A capsule-in-capsule dosage form with bismuth subcitrate and metronidazole in the external capsule and tetracycline and omeprazole in the internal capsule inhibited this degradation.

Examples of marketed dosage forms  

There are several products in the market that have been formulated as bilayer tablets and combination fill capsules to resolve the incompatibility issues. Following are a few examples.  

Brand Name  Manufacturer  Drugs  Dosage form  Application 
Amlopres-Z  Cipla Ltd.  Losartan potassium and amlodipine  Bilayer tablets  Hypertension 
Biotel40-H  Biochemix Healthcare Pvt. Ltd.  Telmisartan and Hydrochlorthiazide  Bilayer tablets  Hypertension 
Coarsucam  Sanofi-Aventis  Amodiaquine hydrochloride and Artesunate  Bilayer tablets  Antimalarial 
Twynsta  Boehringer Ingelheim
Pharmaceuticals Inc 
Telmisartan, Amlodipine  Bilayer tablets  Hypertension 
Trinomia  Gebro Pharma GmbH  Aspirin, Ramipril, and Atorvastatin  Pills in capsules  Cardiovascular diseases 

 

Takeaway  

Incompatibility among FDCs can result in degradation, safety, and bioavailability issues. Multilayer tablets and capsules with combination fills can be the primary options to avoid incompatibility issues in FDCs so that the APIs can be administered in a single dosage unit.  These dosage forms are suitable for oral administration and economical production and further ensure patient compliance and therapeutic success of FDCs.

References 
  1. Hens, B., et al., Development of FixedDose Combination Products Workshop Report: Considerations of Gastrointestinal Physiology and Overall Development Strategy. 2019, Springer. 
  2. Dhiman, N., et al., Development of bilayer tablets with modified release of selected incompatible drugs. Polim Med, 2016. 46(1): p. 5-15. 
  3. Moon, C. and E. Oh, Rationale and strategies for formulation development of oral fixed dose combination drug products. Journal of Pharmaceutical Investigation, 2016. 46(7): p. 615-631. 
  4. Menditto, E., et al., Patient centric pharmaceutical drug product design—The impact on medication adherence. Pharmaceutics, 2020. 12(1): p. 44. 
  5. Rama, M.R.B., Formulation and Evaluation of Bilayer Tablets of Two Incompatible Drugs Amlodipine Besilate and Losartan Potassium. Int. Res. J. Pharm, 2013: p. 136-142. 
  6. Silva, A., et al., Segregated delivery of rifampicin and isoniazid from fixed dose combination bilayer tablets for the treatment of tuberculosis. Journal of Pharmaceutical Research International, 2014: p. 1781-1801. 
  7. Kathpalia, H., K. Sharma, and G. Doshi, Recent trends in Hard Gelatin capsule delivery System. Journal of Advanced Pharmacy Education & Research Apr-Jun, 2014. 4(2). 
  8. Pryce, N.A., et al., Design and Evaluation of a New Fixed-Dose Immediate Release Capsule of Atenolol, Enalapril Maleate and Hydrochlorothiazide. Journal of Pharmaceutical Research International, 2017: p. 1-16. 
  9. Sanso, G., Double capsule for the administration of active principles in multiple therapies. 2002, Google Patents. 

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