04/11/2023 1

Seminar on

POLYMORPHISM(AS A PART OF PREFORMULATION STUDY)

Guided by : Mrs. Hiral Shah

Assistant Professor

Dept. Of Pharmaceutics

Prepared by :

Henil Patel

M.Pharm Sem 1

Pharmaceutics.

04/11/2023 2

List of contents

1. Definition

2. Need to study polymorphism ( rational for selecting polymorph)

3. Properties

4. Types of polymorphism

5. How to differentiate them

6. Pseudopolymorphism.

7. Method for identify polymorphism

8. Parameter to be cared by preformulator

9. Factor affecting polymorphism

10. Effect of polymorphism on bioavailability

11. Application

12. Conclusion

13. references

04/11/2023 3

Definition

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.

04/11/2023 4

Cont…

Thus it is defined as the ability of substance to exist as two or more Crystalline phase that have different Arrangements or conformations of the molecule in the crystallatice .

04/11/2023 5

Need to study polymorphism

• Depending upon their relative stability, 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.

• Only 10% of the pharmaceuticals are present in their metastable form.

Cont..

04/11/2023 6

• Polymorphism is remarkably common particularly within certain structural group.

• E.g. –

Cont..

CLASS %OF POLYMORPHISM

Barbiturates 63

Steroids 57

Sulphonamides 40

04/11/2023 7

• The effect of polymorphism on bioavailability is the most important consequence for drug substance if the bioavailability is mediated via dissolution.

• The example is chloramphenicol palmitate.• Other like novobiocin , griseofulvine , Carbamazepine , aspirin and

ampicilline .• The polymorphism of the excipients may also play an important role in

bioavailability.

Latest example is :- HYDOISOINDOLIN

( a tachykinine receptor antagonist )

Cont..

04/11/2023 8

Stability characteristics

• Depending upon relative stability there are two form of polymorphs 1) stable form 2) meta form .

• Stable form having least aqueous solubility.• Meta form having high aqueous solubility.• Solubility ratio =solubility of metastable form/solubility of stable form.• From below example, we can say that solubility ratio is higher than one

just because of …• relative higher solubility of metastable form, that leads to increase

Cont..

04/11/2023 9

Compound Solubility ratioglybuzole(37) 1

Tetracycline 1

Carbamazepine 1.2

Succynil sulfathiazole 12.7

Niclosamide 22.9

Cont..

04/11/2023 10

Dissolution behavior of the polymorphs

• the absorption rate and bioavailability of drug administered orally is controlled by many factor.

• among which dissolution rate is one of the most important.

• as the thermodynamic activity of polymorph is lower there is lower apparent solubility and thus absorption is also less.

• Order of dissolution rate: Amorphous>metastable> stable

cont..

04/11/2023 11

FORMATION OF METASTABLE POLYMORPHS:-

• Preparation of metastable polymorphs requires, • Supersaturating conditions for the metastable form.• Crystallization of the metastable state before the stable polymorph forms.• Stable conditions for the metastable polymorph so that conversion to the

stable form is prevented .

04/11/2023 12

Properties of polymorphs

Polymorphs show the same properties in the liquid or gaseous state but they

behave differently in solid state. Melting and sublimation temperature. Vapour pressure Solubility and dissolution rate Stability Optical and electrical property Crystal habit Hygroscopicity Heat capacity Solid-state reaction Conductivity Compression characteristics

04/11/2023 13

Type of polymorphism

TYPE

1. ENANTIOTROPIC POLYMORPH

2. MONOTROPIC POLYMORPH

04/11/2023 14

• Phase transition: the process of transformation of one polymorph into another.

• which may also occur on storage or during processing, is called phase transition.

• ENANTIOTROPHS:- If one form stable over certain pressure and temperature range, while the other polymorph is stable over different pressure and temperature range.

• eg, sulfur

04/11/2023 15

• MONOTROPHS:- only one polymorph is stable at all temperature below the melting point, with all other polymorph being unstable.

• E.g. glyceryl stearate , chloramphenicol palmitate .

Both enantiotropism and monotropism are important properties of polymorphs.

04/11/2023 16

Difference between enantiotropy and monotropy.

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.

04/11/2023 17

PSEUDOPOLYMORPHISM

• 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.

04/11/2023 18

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.

04/11/2023 19

Method to identify polymorphism

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 direction• Anisotropic crystal have 2 or3 different light velocities or refractive

indices.• Video recording system and polarizing microscope fitted during according

to heating and cooling stage for investigating polymorph.

cont…

04/11/2023 20

APPLICATION• To study of degree of stability of metastable form.• Transition temperature• Melting point• Rate of transition under various thermal and physical condition.• Whether to peruse polymorphism as a route to an improved dosage form.

04/11/2023 21

Hot stage microscopy

• Fluid stage transformation as a function of temperature is observed• Silicon 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.

04/11/2023 22

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.

04/11/2023 23

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

04/11/2023 24

Differential Thermal Analysis (DTA)

• The advantage is that the sample size required is only 2-5mg .• DTA measures the tempt difference between sample and reference as a

function of temperature or time when heating at constant rate. • A DTA consists of a sample holder comprising thermocouples, sample

containers and a ceramic or metallic block; a furnace; a temperature programmer; and a recording system.

• The key feature is the existence of two thermocouples connected to a voltmeter.

• One thermocouple is placed in an inert material such as Al2O3, while the other is placed in a sample of the material under study.

• As the temperature is increased, there will be a brief deflection of the

voltmeter if the sample is undergoing a phase transition.

04/11/2023 25

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.

04/11/2023 26

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

04/11/2023 27

Applications of DTA / DSC in preformulation studies

1. 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.

04/11/2023 28

Thermo Gravimetric Analysis (TGA)

• is a type of testing that is performed on samples to determine changes in weight in relation to change in temperature.

• Such analysis relies on a high degree of precision in measurements: weight and temperature change.

• As many weight loss curves look similar, the weight loss curve may require transformation before results may be interpreted.

04/11/2023 29

• TGA is commonly employed in research and testing to determine characteristics of materials such as polymers, to determine degradation temperatures, absorbed moisture content of materials, the level of inorganic and organic components in materials, decomposition points of explosives, and solvent residues.

• It is also often used to estimate the corrosion kinetics in high temperature oxidation.

• TGA Q 500.

04/11/2023 30

Dilatometry

• Measure change in volume caused by thermal or chemical effect.• Using dilatometry the melting behaviour of Theobroma Oil was studied. • Extremely accurate but tedious , time consuming and not widely used.

04/11/2023 31

Melting point

• M.P. determination are often useful technique, but only when substance undergoing investigation heated through phase transition without decomposition.

04/11/2023 32

Parameter to checked by preformulator

1. No of polymorphs

2. Relative degree of stability

3. Presence of glassy state

4. Stabilization of metastable form

5. Temperature stability range

6. Solubility of each polymorph

7. Method of preparation

8. Effect of micronization

9. Excipients incompatibility

04/11/2023 33

Factor affecting polymorphism

A) Temperature and Humidity:-• Storage conditions affect physicochemical reaction which are accelerated

at higher temperature.• Humidity acts as a catalyst on the solid surface.• E.g.

1. Zanoterone the solid degradation rate of form 4 is found to be greater than that of form 3 at 40 °C/ 25 %RH and 40°C/75% RH. At 40 °C/ 25 %RH , the rate of degradation is 4 fold higher for form 4 vs 3.

2. Polymorphic transformation of cocoa butter occur after heating.

04/11/2023 34

B) Photostability

• Generally light sensitive drug are protected form the photolytic degradation by packing them suitable in light resistant container.

• Stable crystalline form resist photochemical degradation and does not require light resistant system.

E.g.

1) Acetametacin alpha, beta – stable

gamma - unstable.

04/11/2023 35

C) Effect of solvent

• Solvent can bring dramatic change in growth mechanism and morphology.• Kinetic of crystal growing form solution was determined by two important

factors.

a. degree of molecular roughness

b. nature of absorption of the solvent from surface.

04/11/2023 36

D) Effect of grinding

• Grinding process reduces particle size, so increasing specific surface area and that why direct effect on dissolution rate and bioavaibility of the formulation.

• During process solid state polymorphic transformation in to non crystalline or metastable form is caused by mechanical action.

• E.g.- dihydrate form is more stable than anhydrous form. With increasing grinding time compound become unstable because grinding weakened bonding crystals and water molecules.

04/11/2023 37

E) Effect of tablet compression:-

• Stability and compaction behavior form of of the polymorphic form of drug is important

• Phenylbutazone in which form 3 converted to 2 form at >2000kg/cm2.

04/11/2023 38

Effect of polymorphism on bioavailability

If the absorption of active ingredient in drug through G.I.T. is dissolution rate dependent then 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

novobiocin is used as sodium salt which is active orally but unstable chemically while insoluble form is stable chemically and orally inactive.(unabsorbable )

04/11/2023 39

APPLICATION1. The knowledge of solid-state properties in an early stage of drug development helps to avoid

manufacturing problems, to fine-tune the performance of drugs and provides space for innovations .

e.g.- Famotidine which is an excellent histamine

H2 receptor antagonist is also found to exist in two different polymorphic forms, metastable polymorph B and stable polymorph A.

2. For improvement of therapeutic activity of drug.

3. To prevent loss of raw material.

4. For better bioavailabity of drug.

.

04/11/2023 40

Conclusion

• Differences 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 sable form .

• As polymorphism can have such serious consequences for the

bioavailability of drugs with low aqueous solubility.

04/11/2023 41

Study Question

1. What is polymorphism? Discuss its significance in dissolution.

Enumerate the methods to identify polymorphs. 6 mark ( GTU July 2012 )

04/11/2023 42

References

1. The theory and practice of industrial pharmacy by- Leon Lechman , Joseph L Kanig .

2. Biopharmaceutics and pharmacokinetics by- DM Bhramankar , Sunil Jaiswal .

3. Physical pharmacy by- Alfred Martine.

4. The science of dosage form design by Michael E Alton .

5. Encyclopedia of pharmaceutical technology .

04/11/2023 43

Thank you