**5.1 Physical incompatibility**

In such an instance, active pharmaceutical ingredient and excipients interact without undergoing changes involving like breaking or formation of new bonds. The resulting drug product retains its original chemical properties but may involve changes such as alteration in physical properties. Such interaction results in changes like change in color, odor, flow properties, and sedimentation rate. Such an example of physical incompatibility is between tetracycline and calcium carbonate. It results in formation of insoluble complex with calcium carbonate, leading to slower dissolution and decreased absorption in the gastrointestinal tract [15].

## **5.2 Chemical incompatibility**

In such incompatibility, there is interaction of active pharmaceutical ingredient and excipient through chemical degradation pathway. The chemical reaction involves bond breakage or new bond formation to produce an unstable chemical entity. Chemical reaction may take place as hydrolysis, oxidation racemization, and Maillard reactions. The resulting changes are more deleterious than physical incompatibility. This type of incompatibility can be assessed by chromatographic studies. One of the classical examples of chemical incompatibility is exhibited by reaction of lactose with amino group of active pharmaceutical ingredient referred to as "Maillard reaction" and results into darkening of formulation with characteristic odor. Classical example is of a bronchodilator aminophylline, in which ethylenediamine moiety is reduced by lactose and as a result brown discoloration appeared in samples containing 1:5 (w/w) mixtures of aminophylline and lactose after storing at 60°C for 3 weeks [16].

### **5.3 Therapeutic incompatibility**

Such interaction is also referred to as biopharmaceutical interaction, but it differs from previously discussed incompatibilities in a way that interaction will take place once the formulation is administered into the body. Such type of incompatibility is associated with alteration in drug absorption in the body. In other way, one can say that interaction is taking place between excipient, active component, and physiological fluid. One of the classical examples of such incompatibility is interaction of enteric coated polymers, when administered along with antacids. In such an event, they dissolve prematurely and release the drug that is liable to acid degradation or may cause adverse effect in GI, that is, gastric bleeding associated with NSAIDs [17].

There are specific methods that are employed to determine the existence of incompatibility between excipient and the active pharmaceutical ingredient. Out of all analytical techniques, thermal methods of analysis can provide most positive outcome. In association with thermal methods of analysis, spectroscopic techniques like X-ray diffraction and infrared spectroscopy can provide sideline assistance. High-performance liquid chromatography and thin-layer chromatography provide the more suitable way of studying chemical incompatibilities and provide qualitative and quantitative assessments.
