**3. Determination of chemical properties**

Determination of chemical properties indicates the absorption behavior as well as stability of a molecule in the body. One of the most widely determined chemical properties includes partition coefficient (Log P), dissociation constant (pKa or pKb), and stability of molecule under a variety of conditions. Each property has significant value in development of formulation.

#### **3.1 Partition coefficient**

Partition coefficient (Log P) value is defined as ratio of unionized drug distributed between aqueous and organic phase. Oil-water partition coefficient gives the idea about drug's ability to cross the lipidic membrane. Lipophilic/hydrophilic balance is one of the most important contributing factors for optimum drug

absorption and delivery. Due to lipidic nature of biological membrane, the amount of drug absorbed depends heavily on its lipophilicity. It is the unionized form of molecule that has better lipophilicity and hence it has received so much importance.

$$\text{Log P} = \left(\frac{\text{Coil}}{\text{Cwater}}\right) \text{equilibrium} \tag{1}$$

If the value of Log P is 0, it indicated that drug has equal distribution in water and partition solvent. Value of Log P less than 1 is indicative of higher water solubility and value greater than 1 is indicative of higher lipidic solubility. For optimum solubility and absorption, a proper hydrophilic-lipophilic balance is necessary.

Determination of Log P value in biological system is next to impossible task, so several methods are available to determine partition coefficient of molecule in vitro, which are as follows:


Highly used method is shake flask method that utilizes octanol-water system to determine drug's partitioning behaviors. There are several reasons behind selection of octanol as partitioning solvent, which can be explained as follows:


#### **3.2 Dissociation constant**

Like partition coefficient, dissociation constant (pKa) is the property that determines the solubility in pH-dependent environment and extent of ionization. It is the extent of ionization that determines the absorption as only unionized form can be absorbed and hence it becomes essential to determine the pKa value of molecule. pKa value determination gives idea about site of absorption.

Weakly acidic drugs having pKa value around 4 are best absorbed from stomach as they are predominantly present in unionized form. Basic drugs having pKa value of around 8 are best absorbed from intestine as they are predominantly present in unionized form. % ionization can be determined by the following equation:

$$\text{\(\%Iormization\)} = \left\{ \frac{10^{\left(\text{pH}\cdot\text{pKa}\right)}}{1 + 10^{\left(\text{pH}\cdot\text{pKa}\right)}} \right\} \times \text{100} \tag{2}$$

**9**

**Table 1.**

*Preformulation Studies: An Integral Part of Formulation Design*

One of the most silent chemical parameters that define the pharmacological activity is the type of isomer. Many molecular entities exist in racemic form, but only one form gives the desirable pharmacological activity. Other present isomer may be devoid of pharmacological activity or may exhibit deleterious side effects. Most of us are known to teratogenic tragedy of thalidomide. Thalidomide exists as racemic form. Racemates contain equal amount of enantiomer, which are known as either levorotatory (−) or dextrorotatory (+) based on its ability to rotate the plane

It was introduced as a sedative agent. The S-enantiomer of thalidomide was a teratogenic agent, while R-enantiomer was effective as a sedative agent. Lack of knowledge about chiral selectivity leads to disastrous consequence. In recent times, single enantiomer is dominating the market over the racemate form due to better pharmacological performance. Nowadays, racemic switching or chiral switching is used in which racemic mixtures are developed as single enantiomers. Several single enantiomers are preferred over racemic form (e.g., levofloxacin (ofloxacin), esomeprazole (omeprazole), escitalopram (citalopram), and deslo-

Overview of the same is given in **Table 1**. For better clinical performance of the molecule, it has become necessity to study the chirality of the molecule. In most of the cases, it can be studied by optical rotatory dispersion and circular

The main objective of determining stability of molecule is to identify the conditions in which molecule is susceptible to deteriorate and to determine degradation pathway. The mechanism of degradation and condition provides the idea about proper designing of formulation, suitable molecular modification, appropriate

**Advantage offered**

Ibuprofen S(+)-enantiomer (S)-ibuprofen is over 100-fold more potent inhibitor of

Salbutamol Levalbuterol Racemic for and S-enantiomer hyperresponsiveness in

than racemic mixture

Enhanced activity against pneumococci

Less sedative action with same activity

patients with GERD with least variability

the equivalent dose of the racemate

and lesser GT-related side effects

Reduction is dose of ketoprofen (half) with same effectiveness

cyclooxygenase. So three times dose reduction was achieved

sensitized patients with loss of bronchodilator activity. (*R*) salbutamol produces significantly greater bronchodilation than

Esomeprazole has lower first-pass metabolism and shows better bioavailability than R-eneantiomer and maintains pH above 4 in

storage condition, and selection of proper packaging material.

**Used active enantiomer**

S(−)-enantiomer

R(−)-enantiomer

S(+)-enantiomer

S(+)-enantiomer

Ofloxacin Levofloxacin

Cetirizine Levocetirizine

Ketoprofen Dexketoprofen

Omeprazole Esomeprazole

*Advantage of racemic switching.*

*DOI: http://dx.doi.org/10.5772/intechopen.82868*

**3.3 Chirality**

of polarized light [6].

ratadine (loratadine)) [7].

**3.4 Stability of molecule**

dichroism [8].

**Drug in racemic form**

Most of the strong acids and strong bases are present in ionized form throughout GIT and hence poorly absorbed. But it is also true that most of the pharmaceutical entities are derivatives of weak acids and weak bases and hence absorption is not an issue.
