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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