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 1
st
year
MCOPS
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
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 drug
product

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.


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)

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 an
overall porosity nearly equal to those of tablets prepared with the
original materials.
Example of considerable pharmaceutical relevance:
THERMODYNAMICS OF POLYMORPHISM
Polymorphs are categorized into two types, monotropes and enantiotropes,
depending upon their stability with respect to the range of temperatures and
pressures.



Gibbs free energy vs Time
A dimorphic system
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



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
Influence of polymorphism on pharmaceutical properties
of drugs
Influence on Melting Point
Influence on hygroscopicity
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
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
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.


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 drug
product. The effect of polymorphism on pharmaceutical processing
also depends on the formulation and the manufacturing process.

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.

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 the
structure

may be difficult to prepare single crystals

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
Raman spectra of selected region of two polymorphs of acetaminophin
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.