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8/12/2019 POLYMORPHISM Evaluatory

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IMPORTANCE OF POLYMORPHISM IN

PHARMACEUTICAL INDUSTRY

THERMODYNAMICS OF POLYMORPHISM,

EFFECT OF POLYMORPHISM ON DRUG PROPERTIES AND

ACTIVITY,EVALUATION OF POLYMORPHS

GUIDED BY

DR S.D. VACHALA

DEPARTMENT OF PHARMACEUTICAL CHEMISTRY

MCOPS

SUBMITTED BY

ASHUTOSH TIWARI

120602002

M pharm 1styearMCOPS


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Polymorphs are different crystalline forms of the same pure substance in which

molecules have different molecular conformations.

They have different physical and chemical properties.

POLYMORPHISM


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IMPORTANCE OF POLYMORPHISM IN PHARMACEUTICAL INDUSTRY

Polymorphic forms of a drug substance can have different chemical and physical

properties,including melting point, chemical reactivity, apparent solubility,

dissolution rate, optical and mechanical properties, vapor pressure, and density.

These properties can have a direct effect on the ability to process and/or

manufacture the drug substance and the drug product, as well as on drug product

stability, dissolution, and bioavailability.

Thus, polymorphism can affect the quality, safety, and efficacy of the drugproduct


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Different forms have different physical behavior, especially different solubility

and dissolution kinetics.

Regulatory authorities demand intensive investigations to find potential forms and

especially to characterize them, rank them with regard to their stability, and control

the registered form.

It is vitally important that companies control the desired polymorph during many

years of production; losing this control can cause severe problems.

Knowing as many polymorphs as possible enables selection of the appropriate one

for development and sometimes ensures freedom to operate and perhaps prolong

the patent life of a drug.


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The industry took note of this in 1998 when Abbott Laboratories had

to halt sales of its HIV protease inhibitor, Norvir.

It had commercialized a metastable form of ritanovir, the active

pharmaceutical ingredient (API), in solution-filled gelcaps.

When a more stable, previously unknown polymorph suddenly

crystallized, the company had to reformulate the drug, which cost it an

estimated $250 million in lost sales.

Ritonavir (Norvir)


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The lactose used as an excipient in pharmaceutical tablets and

capsules is a-lactose monohydrate.

It was found that thermal dehydration of this species or

desiccation of a-lactose containing methanol yielded a stable

product with superior binding properties and excellent flowability.

Tablets prepared by compaction of the stable product had anoverall porosity nearly equal to those of tablets prepared with the

original materials.

Example of considerable pharmaceutical relevance:


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THERMODYNAMICS OF POLYMORPHISM

Polymorphs are categorized into two types, monotropes and enantiotropes,

depending upon their stability with respect to the range of temperatures andpressures.

Gibbs free energy vs Time

A dimorphic system


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If one of the polymorphs is stable (i.e., has lower free energy content

and solubility) over a certain temperature range and pressure, while the

other polymorph is stable over a different temperature range and

pressure, then the two polymorphs are said to be enantiotropes

For an enantiotropic polymorph


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Some-times only one polymorph is stable at all temperatures below

the melting point, with all the other polymorphs being unstable.

These polymorphs are said to be monotropes

For a monotropic polymorph


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Influence of polymorphism on pharmaceutical properties

of drugs

Influence on Melting Point


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Influence on hygroscopicity


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Powder dissolution rate curves for two polymorphs of nitrofurantoin. The significance

of the curves for this system is that the retarded initial dissolution rate for the a-

polymorph may render it more favourable for pharmaceutical formulation since there

is evidence that adverse side effects may be associated with rapid absorption of the b-

polymorph


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Whether drug product BA/BE can be affected by the differences in

apparent solubilities of the various polymorphic forms depends on the

various physiological factors that govern the rate and extent of drug

absorption including gastrointestinal motility, drug dissolution, and

intestinal permeability

Influence on bioavailability


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For a drug whose absorption is only limited by its dissolution,large differences in the apparent solubilities of the various

polymorphic forms are likely to affect BA/BE.

On the other hand, for a drug whose absorption is only

limited by its intestinal permeability, differences in the

apparent solubilities of the various polymorphic forms are

less likely to affect BA/BE.


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Influence on Manufacturing of the Drug Product

Drug substance polymorphic forms can exhibit different physical and

mechanical properties, including hygroscopicity, particle shape,

density, flowability, and compactibility, which in turn may affect

processing of the drug substance and/or manufacturing of the drugproduct. The effect of polymorphism on pharmaceutical processing

also depends on the formulation and the manufacturing process.


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Influence on Stability

The most stable form of the drug substance is often

chosen during development, based upon its minimal

potential for conversion to another form and upon its

greater chemical stability.


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EVALUATION OF POLYMORPHS

Powder X-ray Diffractometry (PXRD)

gold standard for phase ID

preferred orientation; interference from crystalline

excipients

Single Crystal XRD

ultimate phase ID with in depth understanding of thestructure

may be difficult to prepare single crystals


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DSC: Differential Scanning Calorimetry

information in phase transition and interaction with excipients

black box: no information on the nature of the transition

interference from both crystalline and amorphous excipients

TGA: Thermo Gravimetric Analysis

quantitative information on the stoichiometry of solvates/hydrates

interference from water-containing


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REFERENCES

Crystallization of Organic Compounds, An Industrial

Perspective- Hsien-Hsin Tung, Edward L. Paul, Michael Midler,

James A. McCauley.

Designing Robust Crystallization Processes for Active

Pharmaceutical IngredientsFrom Art to

Science- Dierk Wieckhusen.

Solid-State of Pharmaceutical Compounds: Impact of the ICH

Q6 guideline on industrial development- D. Giron, M. Mutz

and S Garnier

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