**Artificial intelligence-based models (In silico):**


The human epithelial colorectal carcinoma cells-based model is known as the Caco-2 monolayer assay for permeability assessment. This is a diversified in-vitro permeability assay that covers P-glycoprotein efflux transporters, a variety of enzymes like esterases and peptidases, and tight cellular junctions that resemble the small intestine. These in-silico methods are applied to assess drug permeability with the ability to filter massive amounts of sample data while producing precise and accurate results quickly and accurately. Caco-2 cell permeability approach can be used for in-vitro pharmacokinetic research for oral dosage forms. This cell-based assay is suitable for P-glycoprotein efflux and intestinal enzyme metabolism studies [62].

### **3.5 Stability analysis as per ICH guidelines**

According to ICH (International Conference on Harmonisation) Q1A (R2) regulatory guidelines, the purpose of these guidelines is to test drug substances under different stress conditions such as long-term stability testing, accelerated stability testing for a minimum three different time points, and sometimes the intermediate testing also done for some special cases. These stability testing depend upon the climatic zones where the testing is to be done and follow the criteria of that particular zone. The testing includes the effect of pH temperature, humidity, and photolysis under stress conditions. Stability studies during the preformulation stage are most important to check chemical stability and product degradation for the solid-state and liquid-state formulations [2]. Furthermore, some drugs which are prone to degradation produce toxic substances hence it is important to determine the conditions under which this drug degradation happens. This degradation pattern of the drug substance can suggest a way to mitigate or stabilise or to determine the optimum storage, climatic and shelf-life improvement conditions. The physical observation at product development to check, caking, liquefaction, discolouration, odour, and gel formation. After physical observation, degradation can be identified by mass spectroscopy, HPLC or DSC, NMR, FTIR or other relevant sophisticated analytical techniques.

#### *3.5.1 Photostability*

The photostability standard conditions are well mentioned in ICH-Q1B guidelines. The photostability of drug substances and drug products must be understood to specify handling, packaging, labelling, adverse effects analysis, and to consider innovative formulation strategies. The optimum exposure for simulation during drug manufacture is casually 1.2 million lux as per the European Federation of Pharmaceutical Industries Expert Working Group. Further, during drug/API manufacture, the cumulative exposure of the compounds can be accepted as 100 Klux of visible light without UV exposure, however, the ICH guideline is not applicable here and this data may be helpful for internal audits.

#### *3.5.2 Solid-state stability*

When it comes to solid-state stability, environmental elements including temperature, light, and moisture, as well as the packing materials that come into contact with the dosage form, are the first to have an impact on drug stability. Excipients may affect different chemical interactions with the drug/formulation if selected improperly. The excipients' bound or free moisture, pH, and microclimate can start the deterioration of the dosage forms. Therefore, excipients with low moisture content and low hygroscopicity are preferred for medications that are resistant to hydrolysisinduced deterioration. Various physical properties of the drug molecules like particle shape, size, and surface area, morphology, presence of impurities can play a significant responsibility in drug degradation, either alone or in the presence of excipients [63]. For heat-sensitive drug substances, the processing conditions should maintain at low-temperature conditions to escape from drug degradation. It is possible to use a variety of unique formulation techniques, such as multi-layer particles in capsules or tablets, tablets with moisture-proof coatings, compression coating, tablets inside tablets, or tablets inside capsules. Stressed settings, such as high-temperature studies,

#### *Preformulation Studies: A Versatile Tool in Formulation Design DOI: http://dx.doi.org/10.5772/intechopen.110346*

high humidity, exposure to high wetness, and high-intensity light environments, can be used to assess the solid-state stability of an active substance. It provides an early warning of stability issues that could affect product development [61].

As a case study, published by Carney et al. the degradation pattern of Ciclosidomine in solution due to temperature, buffer constituents, and ionic strength are described. The first-order hydrolysis rate appears in absence of light, again at pH 3.0, 5.0, and 6.0 with the absence of light and in presence of air or nitrogen, reported drug degradation. Hence, optimum light and air conditions should be maintained during small-scale and manufacture stages [14].
