**4. Chemical properties optimization**

#### **4.1 Hydrolysis**

Hydrolysis reactions are very commonly observed chemical reactions responsible for drug degradation due to the high dipolar water molecules availability which binds to the drug molecules and leads to hydrolysis. It involves nucleophilic reaction the of the labile group [67]. The PH can be adjusted to stop hydrolysis. Since the majority of drugs are weak acids or bases in compositions. Formulate the drug solution so that it has a pH that will ensure its stability, add a water-soluble solvent to the formulation, use the optimal buffer concentration to prevent ionisation, or add a surfactant to stabilise against enzyme catalysis. Drug solubility decreased by creating less soluble salts or esters of the drug which are susceptible to ester hydrolysis. The carbonyl functional groups of esters, lactones, amides, lactams, carbamates and imides are susceptible to hydrolysis. By adjusting the pH conditions of liquid dosage form its shelf life can be lengthened however, stability and solubility should not be compromised.

The hydrolysis problem can be prevented by different approaches, such as drug hydrolysis should be checked to stop drug degradation and this can be achieved with the addition of bulky alkyl groups near the functional group by chemical modifications to hinder the action of a nucleophile or enzyme and decreases drug hydrolysis. Similarly, the labile ester functional group is replaced with urethane or amide can increase chemical and metabolic stability [68].

#### **4.2 Oxidation**

A high-oxygen environment can be used to examine a drug's oxidation sensitivity. Rapid evaluation is typically feasible in an atmosphere with 40% oxygen. Samples are kept in desiccators with three-way stop cocks, which are then alternately evacuated and submerged in the desired environment. To ensure the desired environment is created, the method is repeated three or four times. The outcomes could be used to decide if the formulation needs an antioxidant or whether the final drug product has to be packaged in an inert environment [67].

#### **4.3 Reduction**

Reduction is a more prevalent mechanism for drug metabolism. Nicotinamide adenine dinucleotide phosphate is necessary for hepatic microsomes to perform a variety of reductive chemical reactions. Cytochrome P450 catalyses the reduction of azo and nitro compounds. Alcohol dehydrogenase converts chloral hydrate to its active metabolite, trichloroethanol. The active metabolite hydrocortisone is produced when prednisolone and cortisone are reduced. Azo dyes are used as colouring additives in drug products or food items and this can be degraded by liver and intestinal flora to create amines [48].

#### **4.4 Chirality**

The chirality determination at the preformulation stage is considered during the drug development strategy. The undesirable enantiomer should be removed from the therapeutic formulation since, in most cases, one of the enantiomers lacks the

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

necessary pharmacological characteristics. When a separation method is available, the inactive form should be eliminated from considerations of cost. Optical activity evaluation for drug molecules is an essential analysis performed during the early discovery process for NCEs. This would suggest the active enantiotropic form of drug molecules. The drug must be in the enantiopure form as it is a legal requirement for IND filing. Therefore, choosing the appropriate enantiomeric form for the market product must be made before IND filling or a patent. As a case study, the Sirolimus [20] branded as Rapamune in liquid solution was marketed by Pfizer and approved in 1999 by the FDA for immunosuppression. Sirolimus contains Phosal 50-PG active ingredient and polysorbate 80 as an inactive ingredient which is nonaqueous. Further, in solid-state Sirolimus is a chiral compound, however, in aqueous solutions, this drug is found in A, B, and C isomers hence the nonaqueous vehicle is selected for drug product development [69].
