Pre-formulation studies

toxicity screening

“Discovery of a new drug entity is a huge milestone in science, and it becomes even more important if it passes ___as the potential benefits outweigh the side effects. .”

availability at the site of action

The ultimate effect of the new chemical entity depends on its ____ once it is administered through the appropriate route in the appropriate form

pharmaceutical and toxicological screening

“A new challenge is offered after successful ____that is to transform potential active new drug entity into a pharmaceutical formulation.”

pre- formulation

the phase of research and development process for an investigation and determination of the physical and chemical properties of a new drug molecule alone or in combination with other excipients to develop a safe, effective, and stable dosage form.

pre- formulation

foundation or the integral part of developing a robust formulation

pre- formulation

the information from these studies dictates many of the subsequent events and approaches in drug development.

pre- formulation

“Learning before doing”

✓ to establish the necessary physicochemical parameters of a new drug entity

✓ to determine the drug kinetic rate profile

✓ to determine drug stability and develop its stability assay

✓ to establish drug compatibility with common excipients - reduce drug excipient incompatibility

✓ to improve drug bioavailability

✓ to formulate and process stable, effective, and quality drugs

✓ to evaluate the performance of the developed formulation

The SECONDARY objective of pre-formulation testing is to generate information useful to the formulator for the formulator to:

1. To develop an optimum dosage form

2. To form desired quality dosage forms

3. To minimize errors in formulation of dosage form.

4. To achieve high degree of uniformity, physiological availability and therapeutic qualities.

Importance of Pre-formulation Studies (4)

1. physicochemical properties

2. bulk characterization

3. solubility analysis

4. stability analysis

4 Pre-formulation PARAMETERS

• colour

• odour

• taste

• nature of the drug

• polarity

• melting point

sub-areas of preformulation research: PHYSICOCHEMICAL TESTS

▪ Polymorphism & Pseudopolymorphism

▪ Hygroscopicity vs. Deliquescency

▪ Fine particle characterization

▪ Powder flow properties

sub-areas of preformulation research: BULK CHARACTERIZATION

▪ Ionization constant-pKa

▪ pH solubility profile

▪ Common ion effect-Ksp

▪ Thermal effects

▪ Solubilization

▪ Partition co-efficient

▪ Dissolution

sub- areas of preformulation research: SOLUBILITY ANALYSIS

▪ Stability in toxicology formulations

▪ Solution stability

▪ pH rate profile

▪ Solid state stability

▪ Bulk stability

▪ Compatibility

STABILITY ANALYSIS

organoleptic properties evaluation

using the 5 organ senses of the body can help establish organoleptic properties of a DS (drug substance)

organoleptic properties evaluation

records include descriptive standard terminologies in describing the appearance, color, odor, and even taste of the DS (drug substance)

• off-white

• cream yellow

• tan

• shiny

organoleptic characters in COLOR

• pungent

• sulphurous

• fruity

• aromatic

• odorless

organoleptic characters in ODOR

• acidic

• bitter

• bland

• intense

• sweet

• tasteless

organoleptic characters in TASTE

color

the inherent chemical structure relating to a certain level of unsaturation

color

its intensity relates to the extent of unsaturation and the presence of the chromophores.

1) off white

2) cream yellow

3) shiny due to boric acid

Some compounds may appear to have color, although it is structurally saturated

Eg: Chinese Paracetamol is yellowish in color

 Also take into consideration the color of the drug with coloring agents to be added to avoid mottling at the final stages of the formulation

no mottling problem

 It should be properly mixed with the excipients so there is__

odor

the drug may exhibit inherent odor characteristics of the major functional group present

odor

It greatly affects the flavor of the preparation or the foodstuff

taste

the most important parameter of the drug.

taste

 considered with respect to patient compliance

appropriate flavors and excipients & by sugar coating

if the taste is considered unpalatable or bitter in taste it should be suppressed by the addition of the

nature of the drugs

plays an important role in the formulation

amorphous and crystalline

nature of the drugs can either be

crystalline

Solids that have a definite geometrical shape

crystalline

characterized by the regular spacing between molecular lattices in the three-dimensional structure

crystalline

bounded by PLANES or FACES, and the planes of the crystal intersect at particular angles

amorphous

have NO sharp melting points

amorphous

formed due to sudden cooling of liquid

amorphous

the most important advantage associated with this form is the higher solubility and, hence, the higher dissolution rate

amorphous

disadvantage is the reduced stability in comparison to crystalline form, so upon storage, these forms tend to revert to a more stable form.

amorphous

 but the risk-to-benefit ratio remains in favor of  this  form and hence is more preferred for product development

crystalline

have sharp melting and boiling points

crystalline

One of the striking advantages of this form is the impeccable stability at the cost of lower water solubility than the amorphous form.

crystalline

For example, Penicillin G as sodium or potassium salt in crystalline form has better stability, stable and therapeutic response than amorphous form.

1. precipitation

2. rapid cooling after melting

3. lyophilization

amorphous is  obtained by techniques like:

1. X-ray, differential scanning microscopy

2. differential thermal analysis

3. hot stage microscopy

4. scanning electron microscopy (most important)

crystalline various techniques are available to study crystallinity; these include:

scanning electron microscopy

most important techniques in crystallinity study

melting point

can be used to identify a substance and to get an indication of its PURITY

solid’s melting point/ freezing point

it is the temperature at which the solid exists in equilibrium with its liquid state under an external pressure of one atmosphere.

melting point range and temperature of complete liquefaction

 valuable indicators of the purity of the solid compound.

melting point range

the interval between the beginning of liquefaction and complete liquefaction

sharp melting point, melts completely over a narrow temperature range of not more than 0.5-1.0 degree celcius

A pure crystalline organic compound usually possesses ___

small amount of impurities

 The presence of even___ usually depresses the temperature at which melting is complete. Usually, it produces a marked increase in the width of the melting point range.

purity

 studies of this  are essential for further studies to be carried out safely

impurities

may make a compound toxic or render it unstable

• TLC, HPLC, GC and Paper chromatography

• HPLC-Impurity Index(II)

• Homogeneity index(HI)

• DTA

• Hot stage microscopy is another technique, along with Gravimetric analysis and Melting point

techniques in purity studies

impurity index

 the ratio of all responses (peak areas) due to components other than the main one to the total area response response

homogeneity index

defined as the ratio of all responses (peak areas) due to the main component to the total area

polarity

“LIKE DISSOLVES LIKE”

non- polar (lipophilic)

 To get across most membranes, the drug must be relatively ___

polar (hydrophilic)

To be soluble in water, a drug must be ___

Lipid soluble

Un-ionized

Non-polar

Absorb

LUNA in polarity stands 

polymorphism

 is the ability of a compound to crystallize as more than one distinct chemically identical crystalline species with different internal lattices or crystal packing arrangements

polymorphs

they are chemically arranged but mainly differ with respect to physical and pharmaceutical properties.

solubility, stability, and therapeutic activity

different types of polymorphs exhibit different types of ___

polymorphic crystal forms

it has become mandatory to have preliminary and exhaustive screening to identify all the __for each drug

temperature, solvent, and time

The type of crystalline species generated depends on__

polymorphism

The occurrence of ____  can not be predicted because it can be induced in many materials under appropriate conditions

polymorphism

Moreover, its absence is difficult to demonstrate by a single specific test

metastable forms

these usually have a faster dissolution rate, apparently greater equilibrium solubility, and considerably greater bioavailability

1. Monotropic polymorphism

2. . Enantiotropic polymorphism

Types of polymorphism

monotropic polymorphism

those for which only one form is stable, irrespective of temperature and pressure, and the metastable form would revert to the stable form with time and by change in temperature and pressure, and the latter

monotropic polymorphism

involves a one-time transition into another form

monotropic polymorphism

often have different melting points, with the most stable form having the highest melting point

monotropic polymorphism

They also exhibit different X-ray diffraction patterns, IR spectra, and dissolution rates

monotropic polymorphism

one great example is the glyceryl stearate

• handling characteristics of the material

• the stability of formulated preparations

• bioavailability

monotropic polymorphism: these differences in properties may affect the

enantiotropic polymorphism

different forms are stable under different external conditions

enantiotropic polymorphism

Changes in temperature and pressure determine the stable form

1. stable polymorph

2. metastable polymorph

With respect to stability and solubility, polymorphs can be classified as:

stable polymorph

one of the most physically stable polymorphic forms and has the highest melting point, lowest energy, and least aqueous solubility

metastable polymorph

is not stable and will revert to the stable form, which has the highest energy, low melting point, and highest aqueous solubility, and hence shows better bioavailability

metastable polymorph

have broader application in developing formulation

polymorphic transition

transition in polymorphic form can be gradual and time dependent, and can be accelerated by an increase in temperature, humidity, or energetic treatment, as in the processing of powder

mixing, milling, and tableting

polymorphic transition:Therefore, unit processes such as____can induce changes in crystal type and, hence, change the drug's physical and potential biopharmaceutical properties.

caking and gritty

The transformation between polymorphic forms can lead to formulation problems

phase transformations

can cause changes in crystal size in suspensions and their eventual caking.

gritty

 Crystal growth in creams as a result of phase transformation can cause the cream to become__

▪ identify polymorph stable in room

▪ stability of polymorph in dosage form

Polymorphism in pre-formulation study aims to:

• Great care is needed to determine

• Need for control of morphic forms

• useful stress test for a drug substance

Control of morphic forms

• which polymorph is present,

• under what condition

• how long will it be stable

Great care is needed to determineble

• ball-mill- test for a defined time 

• check for any change in polymorphic form through DSC analysis.

A useful stress test for a drug substance is to do:

• active ingredients

• excipients

• during production of formulated product

Need for control of morphic forms is necessary during processing of:

1. No. of polymers that exist

2. Relative degree of stability

3. Presence of glassy state

4. Stabilization of metastable forms

5. Solubility

6. Temperature stability range

The parameters of polymorphs to be investigated are:

▪ Solubility

▪ Melting point

▪ Density

▪ Hardness

▪ Compression characteristic

Polymorphs differ from each other with respect to their physical property, such as:➢

Ex: ▪ 1) Chloramphenicol exists in A, B, and C forms; of these B form is more stable and preferable

➢ by a simple experiment in which the polymorphs are placed under the microscope in a drop of saturated solution.

➢ the crystals of the less stable form will dissolve, and those of the more stable form will grow until only this form remains

➢ For drugs with more than two polymorphs, we need to carry out this experiment on successive pairs of the polymorphs of the drug until we eventually arrive at their rank order of stability.

How do we determine which of the two polymorphs is the more stable?

pseudo polymorphism

caused by changes in the crystallization process, results in the inclusion of solvent molecules in the crystal, thereby producing solvates or hydrates

pseudo polymorphism

the crystals differ in properties from the non-solvated sample, just like the different polymorphic form

pseudo polymorphism

different solvates of the same drug can produce different blood concentrations from administered solid oral dosage form, unlike, polymorphs, in which morphic forms with the lowest melting point usually produce the highest blood concentration

highest blood concentration

polymorphs, in which morphic forms with the lowest melting point usually produce the __blood concentration

hot stage microscopy (melting behavior)

Differentiation of pseudo polymorphs can be studied by__

pseudo polymorphism

For example, during the synthesis of ethinylestradiol, crystallization of the final product is achieved by using solvents like acetonitrile, chloroform, methanol, and water. As a result, four different solvates are generated.