Polymorphism

Sagar Kishor Savale

POLYMORPHISM

Mr. Sagar Kishor Savale

Department of [email protected]

2015-016

05/01/2023 1 1

mailto:[email protected]

05/01/2023 Sagar Kishor Savale 2

List of contents:-1. Definition2. Need to study polymorphism ( rational for selecting

polymorph)3. Types of polymorphism4. How to differentiate them5. Pseudo polymorphism6. Properties7. Method for identify polymorphism8. Significance of polymorphism9. Conclusion10. References


Definition1,2

When a substance exists in more than one crystalline form, the different form are designated as polymorphs and the phenomenon as polymorphism.

e.g.:-carbon: diamond in a cubic ( tetrahedral lattice arrangement )Graphite in sheet of a hexagonal lattice.


True polymorphs can be classified into two different types2

1. Enantiotropic— one polymorph can be reversibly changed into another one by varying the temperature or pressure. eg. sulfur

2. Monotropic— the change between the two forms is irreversible. eg. Glyceryl stearates


Difference between enantiotropy and monotropy.3

Enantiotropic pair monotropic pairReversible phase transition Irreversible phase transition

Metastable stable Metastable stable

Transition is endothermic Transition is exothermic

Lower melting form is thermodynamically stable below the transition temp.. And higher m.p . form is stable above the transition temp..

Higher melting form is always thermodynamically stable form.

lower m.p. has lower heat of fusion. Higher m.p. has high heat of fusion.


Method to identify polymorphism.3

Optical crystallography:Use in the identification of polymorphs crystal exist in isotropic and

anisotropic form Isotropic examine the velocity of light is same in all directionAnisotropic crystal have 2 or3 different light velocities or refractive

index.Video recording system and polarizing microscope fitted during according

to heating and cooling stage for investigating polymorph.

cont…


Application

To study of degree of stability of metastable form.Transition temperatureMelting pointRate of transition under various thermal and physical condition.Whether to peruse polymorphism as a route to an improved dosage form.


Hot stage microscopeFluid stage transformation as a function of temperature is observedSilicon oil stage microscopy is used for detection of pseudopolymorph. APPLICATION: in the study of solid-state active pharmaceutical ingredients

(APIs), EXCIPIENTS and pharmaceutically relevant polymers and lipids.


x ray diffraction method

It provide the most complete information about solid state (identification & description)

This method is based on the scattering of x-ray by crystals

By this method one can identify the unit cell dimensions & conclusively establish the crystalline lattice system & provide specific differences between crystalline forms of given compound.

In an X-ray diffraction measurement, a crystal is mounted on a goniometer and gradually rotated while being bombarded with X-rays, producing a diffraction pattern of regularly spaced spots known as reflections.

It is tedious time consuming so it is not used or unsuitable for routine use.


X ray diffraction pattern


Application many materials can form crystals—such as salts, metals, minerals,

semiconductors, as well as various inorganic, organic and biological molecules—X-ray crystallography has been fundamental in the development of many scientific fields


Melting pointM.P. determination are often useful technique, but only when substance

undergoing investigation heated through phase transition without decomposition.


Differential Scanning Calorimetric (DSC) DSC is also like to DTA except that the instrument measures the amount of energy

required to keep the sample at the same temperature as the reference i.e. it measures the enthalpy of transition.

When no physical or chemical changes is occurring within the sample then there is neither a temperature change nor the need to input energy to maintain an isotherm.

Samples that may be studied by DSC or DTA are:Powders, fibers , single crystals, polymer films, semi-solids.

DSC measures endothermic and exothermic transitions as a function of temperature.

–Endothermic heat flows into a sample.

–Exothermic heat flows out of the sample.


Differential Scanning Calorimeter (TA Instruments Q10, Q 100,Q 1000)


Applications of DTA / DSC in preformulation studies 1. To determine the purity of a sample

2. To determine the number of polymorphs and to determine the ratio of each polymorph 3. To determine the heat of solvation .4. To determine the thermal degradation of a drug or excipients .5. To determine the glass-transition temperature(tg) of a polymer.


Effect of polymorphism on bioavailability

If the absorption of active ingredient in drug through G.I.T polymorphism is an important preformulation tool.

Here successful utilization of polymorph having significant greater thermodynamic activity (solubility)may provide good therapeutic blood level from otherwise inactive drugs. Eg novobiocin .

two different forms : crystalline and amorphous. In tablet or capsule formulation


PSEUDO POLYMORPHISM4

Term - pseudo means = false

The phenomenon in which solvent molecules get incorporated into crystal lattice of solid are known as solvates.

This solvates exist in different crystal form called pseuodopolymorph and the phenomenon is called as Pseudopolymorphism .

also known as a hydrate when water is solvent.

E.g.- synthetic estrogen ‘ethynylestradiol ’ is crystallized from the solvent acetonitrile , methanol , chloroform and saturated with water four different crystalline solvates are form.


Differentiate pseudopolymorph form true polymorph.By observing melting behavior in silicon oil using hot stage microscopy.Here in this technique pseudopolymorph evolve the gas causing bubbling of

the oil.While true polymorphs merely melts, forming second globular phase.


Application

1. For improvement of therapeutic activity of drug.

2. To prevent loss of raw material.

3. For better bioavailabity of drug.

.


Need to study polymorphism.5

One of the several polymorphic form will be physically more stable than others.

Stable polymorph represent s the lowest energy state, has highest melting point and least aqueous solubility.

Metastable form represent the higher energy state, have lower melting point and high aqueous solubility .

Metastable form converted to the stable form due to their higher energy state.

Metastable form shows better bioavailability and therefore preferred in formulations.

Cont..


Polymorphism is remarkably common particularly within certain structural group.

E.g. –

Cont..

CLASS %OF POLYMORPHISM

Barbiturates 63

Steroids 57

Sulphonamides 40


Significance of studying polymorphism

Different polymers exhibits different solubility, therapeutic & stability.

The desire forms consistently manufactured.

The effect of pharmaceutical manipulations are understood. E.g. granulation, milling & compression.

Effect of storage condition on the dosage form can be evaluated & predicated. E.g. crystal growth in suspension, cream.


Properties of polymorphs.5

Polymorphs show the same properties in the liquid or gaseous state but they behave differently in solid state. Melting and sublimation temperature.

Solubility and dissolution rate

Stability

Crystal habit

Hygroscopicity

Compression characteristics


ConclusionDifferences in the solubility and melting point must also be assessed and

then a decision can be made to determine which form to progress through to the next stage.

Metastable form may lead to a preferential choice of a polymorph other than stable form .

As polymorphism can have such serious consequences for the bioavailability of drugs with low aqueous solubility.


References1. M.E. Aultan, The science of dosage form design, 2nd edition 2002, p.no

8,26,124-126,142-144.2. Brahmankar D. M., Sunil B. Jaiswal, Biopharmaceutics &

Pharmacokinetics- A Treatise,1st edition, Vallabh Prakashan, New Delhi 2007, p.no-27-29.

3. Leon Lachman, Herbert A. Lieberman, The Theory Practice Of Industrial Pharmacy, 3rd edition, Varghese Publication, Bombay 1987, p.no. 178-181, 230-231.

4. Alfred Martin, James Swarbrick, Physical Pharmacy,3rd , Varghese Publication, Bombay 1991, p.no. 72-73, 575-76.

5. Encyclopedia of Pharmaceutical Technology

Polymorphism

Health & Medicine

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