Preformulation: Solubility Profile of Drugs

Introduction

The maximum amount of solute dissolved in unit amount of solvent in certain conditions of temperature and pH called as solubility. To enter into systemic circulation, the drug is needed to go into the solution form. Solubility profile plays an important role in preformulation study to design a suitable method for obtaining a solution form of the drug in a suitable media. This solution form of drug then passes through biological membrane and enter into systemic circulation to give therapeutic effect. Solubility profile is the detailed information about the solubility characteristics of a drug under various conditions.

Solubility
Solubility

Significance of solubility

  • Increased bioavailability
  • Taste masking
  • Reducing degradation in the GIT
  • Production of sustained released dosage form

Factors affecting solubility of drugs

  • Temperature
  • Physicochemical properties of drug
  • Nature if solvent
  • Acidity and basicity of solution
  • Pressure

Methods to enhance solubility of drug

Changing pH of the solution

In case of weakly acidic drug, the solubility is increased by increasing the pH and for weakly basic drug the solubility is increased by decreasing the pH.

Changing the solvent

If the drug has less solubility in water, then water may be replaced by either partially or completely with one or more water soluble solvents like ethanol, sorbitol. These solvents are called as cosolvents. And the phenomenon is known as cosolvency.

Changing the polymorphs

Metastable polymorphs show better solubility than stable polymorphs. Hence by converting stable polymorph to metastable polymorph we can increase the solubility.

Addition of suitable surfactants

If the concentration of surfactant is increased over the Critical Micelle Concentration (CMC), the partition of the drug into the micelle increases which increases solubility of drug. Micelles are the aggregation of surfactant molecule in a solution and CMC is the concentration at which molecules organized into micelle form.

Solubilization

Solubilization is the process by which solubility of poorly soluble substance is increased by using surfactants.

Intrinsic solubility (S0)

Intrinsic solubility is the natural solubility of substance in specific solvent under certain conditions. It represents the maximum amount of solute that can dissolve in a solvent at equilibrium without the presence of any external factors influencing the solubility. This is the fundamental solubility of drug when it is completely unionized.

For a weak acid the intrinsic solubility is the solubility of the drug determined in a strongly acidic solution. For a weak base it is determined in strongly alkaline solution.

Description Part of solvent required for one part of solute
Very solubleLess than 1
Freely solubleFrom 1 to 10
SolubleFrom 10 to 30
Sparingly solubleFrom 30 to 100
Slightly solubleFrom 100 to 1000
Very slightly solubleFrom 1000 to 10000
Insoluble/practically insoluble10000 and more

Solubility profile

pH and pKa

A large number of drugs are either weak acids or weak bases. The ionization and dissociation of a drug molecule is depended on the degree of ionization. Ionization of a drug molecule is depended on the pH of solution and pKa value. The pH and pKa values are important for study of drug absorption to systemic circulation.

It is important to know the extent to which the molecule is ionized at a certain pH. This property affects the solubility, stability and drug absorption.

The pH and pka values can be obtained by using Handerson-Hasselbach equation. The Handerson-Hasselbach equation provides an estimate of the ionized and unionized drug concentration at a particular pH.

For acidic drug compounds,

HA + H2O = H3O+ + A

pH = pKa + log[ionized]/[unionized]

pH = pKa + log [A]/[HA]

pH= pKa + log [base]/[acid]

Determination of pKa

pKa value can be determined by following methods

  • Potentiometric method
  • Spectrophotometric method
  • Solubility measurements
  • HPLC techniques
  • Conductometric method

Significance of pH and pKa

  • From pKa value we can determine the unionized fraction of drug at a certain pH.
  • With the help of pKa value we can determine the rate of absorption and site of absorption of drug.
  • The pH equation helps to determine the solubility profile of the salt.
  • For acids a pH below the pKa improve the absorption and for bases pH above the pKa improves absorption.

Partition coefficient

Partition coefficient is the measure of distribution of a solute between two immiscible phases typically a lipophilic organic solvent and water. It is a quantitative indicator of how substance distributes itself between these two phases at equilibrium.

Partition coefficient is denoted by log P which can be defined as the concentration of unionized compound between organic and aqueous phases at equilibrium.

Log P = (unionized compound)org / (unionized compound)aq

The octanol-water partition coefficient is most commonly used in the formulation development.

P = (concentration of drug in octanol) / (concentration of drug in water)

Role of partition coefficient in preformulation study

  • A drug substance having logP values between 1 and 3 shows good absorption.
  • If logP greater than 6 or less than 3 have poor transport characteristics.
  • Highly non polar molecules show good bioavailability and highly polar compound shows poor bioavailability.
  • There is parabolic relationship between logP and transport. The chemical compound which has balance between these two properties shows good oral bioavailability.

Methods to determine partition coefficient

  • Shake flask method
  • Counter current and filter probe method
  • Chromatographic method

Conclusion

Solubility study helps to identify the potential bioavailability problem of drug. For example, drug having limited solubility in fluids of GIT shows poor absorption. Solubility profile helps to determine suitable media from which drug will be absorbed. For example, acidic drugs will be absorbed from acidic region and basic drugs will be absorbed from basic region.

Frequently asked questions

What is solubility profile in industrial pharmacy?

Solubility is the important property in dosage form development. Solubility profile is the study of pH, pKa and partition coefficient of drug. The information of solubility profile is helpful to improve bioavailability of drug.

What is critical micelle concentration (CMC)?

Micelles are the aggregation of surfactant molecule in a solution and CMC is the concentration at which molecules organized into micelle form.

 

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