2. Pre formulation studies

▪ Ionization constant-pKa

▪ pH solubility profile

▪ Common ion effect-Ksp

▪ Thermal effects

▪ Solubilization

▪ Partition co-efficient

▪ Dissolution

SOLUBILITY ANALYSIS

solubility analysis

One of the most widely studied techniques during pre-formulation analysis is the solubility profile of the drug candidate

solubility analysis

It is the backbone study of the pre-formulation stage that determines the performance of the developed formulation.

solubility and permeability

they form the scientific basis of the biopharmaceutics classification system (BCS), which can provide a framework for designing the type of drug delivery system.

solubility

The ___of a drug is the amount of the drug that dissolves in a given solvent to produce a saturated solution at constant temperature and pressure

crystal characteristics, temperature, pH, complexation, and molecular structure.

Solubility is not an independent parameter but relies on several properties like ___

good aqueous solubility

For the conversion of drug molecules into an effective oral formulation, they must have____ for better absorption.

solubility: high

permeability: high

BCS class 1

solubility: low

permeability: high

BCS class 2

solubility: high

permeability: low

BCS class 3

solubility: low

permeability: low

BCS class 4

class 1

approaches in formulation development: conventional solid oral dosage form

class 2

approaches in formulation development: use techniques to improve surface area or improving solubility  by addition of cosolvents or surfactants

class 3

approaches in formulation development: use of permeability enhances

approaches in formulation development: use approaches of classes 2 and 3

very soluble

parts of solvent required for one part of solute: less than 1

freely soluble

parts of solvent required for one part of solute: 1-10

soluble

parts of solvent required for one part of solute: 10-30

sparingly soluble

parts of solvent required for one part of solute: 30-100

slightly soluble

parts of solvent required for one part of solute: 100-1000

very slightly soluble

parts of solvent required for one part of solute: 1000-10,000

10,000 or more

parts of solvent required for one part of solute: practically insoluble or insoluble

1. Solution phase equilibrium with solid phase at a stated temperature and pressure.

2. Determine the amount of drug dissolved

3. Determine the amount of drug available for absorption

4. Solubility reduction w/c is carried out in certain conditions

solubility studies are for

• enhancement of chemical

• stability taste masking

• products production of sustainedrelease products

Solubility reduction w/c is carried out in certain conditions, such as:

• Chemical modification of drug

• Addition of cosolvent or surfactant

• Particle size reduction

• Temperature change method

• Hydrotropy

• Complexation

There are several techniques that are available to improve the solubility of drug candidates, which are as follows:

Higuchi-Connors

The equilibrium solubility is based on the phase-solubility technique proposed by___

• Drug dispersed in solvent in a closed container

• agitated at a constant temperature using shakers

• samples of the slurry are withdrawn as a function of time

• clarified by centrifugation and assayed by HPLC, UV, GC

methods in phase- solubility technique

pKa

is the dissociation constant of a drug

un- ionized drug

it is lipid soluble and thus permeates through the lipid membrane

ionized substances

it is lipid insoluble; therefore, permeation is slow

pH, the Henderson Hasselbalch equation

degree of ionization depends on __➢ determined by UV spectroscopy, Potentiometric titration, and the titrimetric method

pKa value determination

gives an idea about the site of absorption.

weakly acidic drugs

having a pKa value around four are best absorbed from the stomach as they are predominantly present in the unionized form

basic drugs

having a pKa value of around eight are best absorbed from the intestine as they are predominantly present in unionized form

solubilization

is defined as the spontaneous passage of poorly water-soluble solute molecules into an aqueous solution of a soap or detergent in which a thermodynamically stable solution is formed

solubilization

the process by which apparent solubility of an otherwise sparingly soluble substance is increased by the presence of surfactant micelles .

micelles

the mechanism desctibes the property of surface active agents to form colloidal aggregates

• Addition of co-solvent to the aqueous system like ethanol, propylene glycol, & glycerin

•  Act by disrupting the hydrophobic interactions at the nonpolar solute/water interface

thermodynamically stable solution is formed

airliquid interface

When surfactants are added to the liquid at low concentration, they tend to orient at the__

bulk of liquid

On further addition of surfactant the interface, becomes completely occupied and excess molecules are forced into the__

CRITICAL MICELLE CONCENTRATION (CMC)

At very high concentration surfactant molecules in the bulk of liquid begin to form micelles and this concentration is know as____

partition coefficient

a measurement of drug lipophilicity or the ability to cross the cell membrane

partition coefficient

represented by (Log P) value is defined as the ratio of unionized drug distributed between aqueous and organic phases

oil-water partition coefficient

gives an idea about the drug’s ability to cross the lipidic membrane.

lipophilic/hydrophilic balance 

is one of the most important factors for optimum drug absorption and delivery

o

if the value of Log P is __, it indicated that drug has equal distribution in water and partition solvent

less than 1

value of Log P ___is indicative of higher water solubility

greater than 1

value___ is indicative of higher lipidic solubility

hydrophilic-lipophilic balance

For optimum solubility and absorption, a proper ___ is necessary

• Shake flask method

• Chromatographic method (HPLC)

• Computation based on software

• Countercurrent/filter probe method

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

partition coefficient

The octanol-water system is widely accepted to explain this phenomenon.

buccal membrane

butanol pentanol system

blood- brain barrier

chloroform-cyclohexane

shake flask method

Drug is shaken between octanol and water

shake flask method

Aliquot is taken and analyzed for drug content

shake flask method

Highly used method that utilizes octanol-water system to determine drug’s partitioning behaviors.

octanol

is believed to mimic the lipoidal character of biological membrane as it contains polar head and nonpolar tail.

octanol

is organic compound that is immiscible with water; however, some of the water is expected to be present in polar head portion.

octanol

Solubility parameter for most of the drugs resembles with that of ___

1. Log P is greater than 5

2. Molecular weight >500

3. There are more than five hydrogen bond donors (number of NH + OH)

4. There are more than 10 hydrogen bond acceptors (number of hydrogen + oxygen )

5. Molar refractivity should be between 40 and 130

For a drug that permeates through passive diffusion, we need to consider the Rule of Five:

pH solubility profile

the solubility of a basic and acidic drug will show differences in solubility with changes in pH

3-4 and at 37 °C temp

pH solubility profile of a drug can be established by running the equilibrium solubility experiment within an ideal pH range of ___

≤ 1mg/ml

if the solubility is__, it indicates the need for salt formation to improve solubility

≤ in pH =1-

if solubility is __7, a pre-formulation study can be initiated

4°C

ensure physical stability

 37 °C

 support Biopharmaceutical evaluation

dissolution

the ability of the drug to dissolve in the fluids at the absorption site

dissolution rate

expresion of D; (rate-limiting step)

DR of a drug is increased by

decreasing the particle size___

highly soluble salt

for a higher dissolution rate- use a ___of the parent substance

faster

The greater the dissolution rate, the __the absorption

Noyes- Whitney equation

This equation is useful for estimating the rate of dissolution and predicting the absorption

1. onset of action

2. intensity of action

3. duration of response

4. control the overall bioavailability of the drug form

Dissolution Rate can affect:

1. Apparatus

2. Dissolution medium

3. Agitation

4. Validation

Dissolution testing considerations

intrinsic dissolution

Intrinsic Dissolution- determined by Noyes-Whitney eq

dissolution testing

dissolution and drug release tests are in- vitro tests that measure the rate and extent of dissolution or release of the drug substance from a drug product, usually aq. medium under specified conditions

dissolution testing

it is an important QC procedure for the drug product and linked to product performance in-vivo

• evaluation of bioavailability

• batch to batch drug release uniformity

• development of more efficacious and therapeutically optical dosage forms

• ensures quality and stability of the product

• product development, quality control, research, and application

need for dissolution testing

dissolution testing

within the time interval specified, or at each of the times stated, withdraw a specimen

1. the basket method (apparatus 1)

2. the paddle method (apparatus 2)

most commonly employed dissolution test methods are

basket and paddle methods

these methods are simple, robust, well standardized, and used worldwide. these methods are flexible enough to allow dissolution testing for a variety drug products

apparatus 1 and apparatus 2

should be used unless shown to be unsatisfactory

• the reciprocating cylinder (apparatus 3)

• a flow- through cell system (apparatus 4)

the in vitro dissolution procedures that described in the USP, may be considered if needed

common ion effect

The suppression of the degree of dissociation of a weak electrolyte containing a common ion makes an insoluble substance more insoluble

common ion effect

if a salt of weak acid or base is added to the solution of an acid or base, the respective dissociation of acid or base is diminished further reducing solubility

Cl-

for example, adding NaCl to a solution of AgCl and H2O, the common ion is

thermal effects

helps to evaluate the drug solubility with respect to the changes in the temperature of the solvent

• temp of the solvent

• nature of solute and solvent

the solubility of a solute in a solvent is dependent on the following:

heat (endothermic)

In the process of dissolution, most of the drug substances absorb__

endothermic

Heat of solution is positive

exothermic

Heat of solution is negative (lithium salts)

heat of solution

effect of temperature on the solubility of drug can be determined by measuring__

heat of solution

it represents the heat released or absorbed when a mole of solute is dissolved in a large quantity of solvent

5, 25, 37, 50 degree celcius

typical temperature range include

determination of temperature effect on solubility helps in predicting storage condition and dosage form designing

importance of determining heat temperature

density

defined as the ratio of the mass of a substance to its volume, which greatly depends on particle size distribution and shape

voids

the main problem that arises when determining bulk volume is the __, which can be interparticulate, open, and closed intraparticulate.