WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

Ethiraj et al. World Journal of Pharmacy and Pharmaceutical Sciences

Volume 3, Issue 3,621-633. Review Article ISSN 2278 – 4357

POLYMORPHISM IN PHARMACEUTICAL INGREDIENTS

A REVIEW

*Ethiraj Thiruvengadam and Ganeshan Vellaisamy

Department of Pharmaceutics, The Erode College of Pharmacy, Erode, Tamilnadu.

ABSTRACT
Article Received on
14 February 2014, When formulating a drug product, physico-chemical stability,
Revised on 28 February 2014 solubility and bio-availability of active pharmaceutical ingredient
Accepted on 13 March 2014
(API) is an important impact. The knowledge of solid-state properties
of API in an early stage of drug development helps to avoid the
*Correspondence for Author
manufacturing defects and to improve its qualities. This makes the
Ethiraj Thiruvengadam
Department of Pharmaceutics, study of polymorphism and crystallization of pharmaceutical
The Erode College of compounds highly important. Now-a-days, most of the drugs are
Pharmacy, Erode, Tamilnadu formulated in crystalline form, so the manufacturing units highly
concentrate on the investigation of crystal polymorphism to optimize
the physico-chemical properties of API before the drug product development. It is necessary
to get knowledge about the polymorphism in order to achieve the rapid absorption of low
solubility drugs in to systemic circulation, to improve the dissolution rate, to assure the
stability of drug and to achieve the bio-availability. This article briefly reviews, the
importance, application of polymorphism in pharmaceuticals, types of crystal systems &
polymorphism and its characterization.

Key words: Cyrstallization, Solubility, Stability and bio-availability.

INTRODUCTION
The investigation of drug polymorphism is an important step in any reformulation study
because polymorphism may have a considerable influence on solid-state properties that may
be modifies biopharmaceutical and technological behavior of drug. Polymorphs are different
crystalline forms of a drug that may have different physicochemical properties and biological
activities. Polymorphism comes from the Greek words, Polus = many and morph = shape.
Thus it is defined as the ability of a substance to exist as two or more crystalline phases that
have different arrangements or conformations of the molecules in the crystal lattice.

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Polymorphism is very important in those areas of chemical research where full

characterization of a material has a pivotal role in determining its ultimate use, e.g., in
pharmaceutical, pigment, agrochemical, explosive and fine chemical industries [1].

IMPORTANCE OF POLYMORPHISM IN PHARMACEUTICALS

 Polymorphism has been recognized as an important element of drug development
 Polymorphic forms of a drug substance can have different chemical and physical
properties, including melting point, chemical reactivity, apparent solubility, apparent
solubility, dissolution rate, optical, electrical and mechanical properties, vapor pressure,
stability, and density.
 These properties can have a direct effect the ability to process and/or manufacture the
drug substance and the drug product, as well as on drug product stability, dissolution, and
bioavailability.
 Polymorphism is very common among pharmaceutical substance and thermodynamic
stability of a polymorph can impact pharmaceutical properties such as bioavailability,
process ability and manufacturability.
 Polymorphic forms possess higher potential energy with respect to the
thermodynamically stable or lowest entry forms.
 Differenent polymorphic phase’s exhibit unique physicochemical properties include
solubility, dissolution rates which can influence bioavailability.
 The ability to isolate, differentiate, and characterize individual polymorphs is a major
challenge to the pharmaceutical industry.

PHARMACEUTICAL APPLICATIONS OF POLYMORPHISM

Purification of drugs: Crystallization is used as a purification process. It is used for removing
impurities from pharmaceutical products, i.e., recrystallization technique.

Better processing characteristics: Crystallization technique is used to change the

micromeritics of drugs such as compressibility and wet ability.

Improved physical stability: Crystalline forms play an important role in product properties
such as suspension stability and hardness of a tablet. Using dehydrating materials such as
dehydrated alcohol and glycerol, the stability of hygroscopic substances can be enhanced.
Ease of handling: Crystallization facilitates various operations such as transportation and
storage.

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Better chemical stability: Crystallization increases the stability of drugs. For example
amorphous penicillin G is less stable than crystalline salt. Amitryptyline is more stable in
crystalline form than in amorphous form.

Improved bioavailability: Some drugs are more effective in their crystalline form. For
example, Penicillin G does not dissolve immediately in the gastric fluids. Therefore, its
degradation decreases. Hence, bioavailability of penicillin G enhances.

Sustained release: Drug substances with different sizes of crystals can be used in the
production of sustained release dosage forms. For example protamines zinc insulin in
crystalline form slowly and continuously release insulin from the site of injection for
prolonged periods [2].

TYPES OF SOLIDS
Solid is one of the three classical states of matter (the others being gas and liquid). It is
characterized by structural rigidity and resistance to changes of shape or volume. The atoms
in a solid are tightly bound to each other, either in a regular geometric lattice (crystalline
solids, which include metals and ordinary water ice) or irregularly (an amorphous solid such
as common window glass).

Crystalline Solids
These solids have a particular three dimensional geometrical structure. The arrangement
order of the ions in crystalline solids is of long order. The strength of all the bonds between
different ions, molecules and atoms is equal. Melting point of crystalline solids is extremely
sharp. Mainly the reason is that the heating breaks the bonds at the same time. The physical
properties like thermal conductivity, electrical conductivity, refractive index and mechanical
strength of crystalline solids are different along different directions. These solids are the most
stable solids as compared to other solids.

Amorphous solids
The strength of different bonds is different in amorphous solids. There is no regularity in the
external structure of amorphous solids. On the other hand, amorphous solids don’t have sharp
melting point. This is due to the variable strength of bonds present between the molecules,
ions or atoms. So, bonds having low strength on heating break at once. But the strong bonds

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take some time to break. This is the reason that the amorphous solids don’t have sharp
melting points.
Amorphous solids are isotropic in nature. Isotropic means that in all the directions their
physical properties will remain same.

Fig 1: Internal arrangement of amorphous and crystalline solids

TYPES OF CRYSTAL SYSTEMS

Crystals are grouped in to two types according to their crystalline structure and physico-
chemical properties.

Table 1 : Crystal grouped by lattices (crystalline structure)

Shape Characteristics
Cubic Three axes of identical length (identified as a1, a2, and a3) intersect at right
angles.
Four axes (three of which are identical in length and denoted as (a1, a2 and
Hexagonal a3) lie in a horizontal plane, and are inclined to one another at 120º. The
fourth axis, c, is different in length from the others, and is perpendicular to
the plane formed by the other three.
Three axes (two of which are denoted as a1 and a2, and are identical in
Tetragonal
length) intersect at right angles. The third axis, c, is different in length with
respect to a1 and a2.
Orthorhombic Three axes of different lengths (denoted as a, b, and c) intersect at right
angles. The choice of the vertical c axis is arbitrary.
Three axes (denoted as a, b, and c) of unequal length intersect, such that a
Monoclinic
and c lie at an oblique angle, and the b axis is perpendicular to the plane
formed by the other two.
Three axes (denoted as a, b, and c) of unequal length intersect At three
Triclinic
oblique angles.

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Table 2 : Crystals Grouped by Properties

Types Characteristics
Covalent A covalent crystal has true covalent bonds between all of the atoms in the
Crystals crystal. Many covalent crystals have extremely high melting points. Examples:
Diamond and Zinc sulfide crystals.
Metallic Individual metal atoms of metallic crystals sit on lattice sites. This leaves the
Crystals outer electrons of these atoms free to float around the lattice. Metallic crystals
tend to be very dense and have high melting points.
Ionic The atoms of ionic crystals are held together by electrostatic forces. Ionic
Crystals crystals are hard and have relatively high melting points. Examples: Sodium
chloride and Potassium chloride crystals.
These crystals contain recognizable molecules within their structures. A
Molecular molecular crystal is held together by non-covalent interactions, like van der
Crystals Waals forces or hydrogen bonding. Molecular crystals tend to be soft with
relatively low melting points. Examples: Rock candy, the crystalline form of
table sugar or sucrose.

Fig 2: Various Types of Solid Forms

Paracetamol, is the most widely used antipyretic and analgesic in the world. Though the drug
seems to be simple, it has been shown to exist in two polymorphic forms. One is monoclinic
Form-I, which is marketed whereas Form-II is orthorhombic.

Piroxicam, a nonsteroidal, anti-inflammatory drug widely prescribed all over the world exists
in three forms I, II and III.

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Table 3: Physical Properties that Differ for each Crystal Forms [3]
Properties Parameters
Molar volume and density
Packing properties Refractive index
Conductivity: electrical and thermal
Hygroscopicity
Melting and sublimation temperatures
Internal or structural energy
Enthalpy
Heat capacity
Thermodynamic properties
Entropy
Free Energy and Chemical Potential
Thermodynamic Activity
Vapor Pressure
Solubility
Spectroscopic properties Electronic state transitions
Vibration state transitions
Nuclear spin state transitions
Dissolution rate
Kinetic properties
Rates of solid-state reactions
Stability
Surface free energy
Surface properties
Interfacial tensions
Crystal habit
Mechanical properties Hardness
Tensile strength

METHODS EMPLOYED TO OBTAIN UNIQUE POLYMORPHIC FORMS

 Sublimation
 Crystallization from a binary mixture of solvents
 Vapour diffusion
 Thermal treatment
 Crystallization from melting
 Rapidly changing solution pH to precipitate acidic or basic substances
 Thermal desolvation of crystalline solvates
 Growth in the presence of Additives
 Griding

SOME SOLVENTS USED FOR CRYSTALISATION

Nearly fifteen organic solvents used in crystallization of 6397 compounds [4].
Solvents Number of Compounds
1) Ethanol 1328

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2) Methanol 1030
3) Hexane 821
4) Ethyl Acetate 573
5) Dichloromethane 402
6) Acetone 394
7) Acetonitrile 379
8) Diethyl ether 346
9) Chloroform 342
10) Toluene 304
11) Benzene 174
12) Water 140
13) Cyclohexane 56
14) DMSO 29

CHARACTERIZATION OF POLYMORPHS
A number of techniques have been used to identify different polymorphic phases of a
compound of methods provides a powerful means for identification and isolation of each
crystalline modification [5].

Optical microscopy: It determines the optical properties (birefringence, indices of refraction,

interference figure, dispersion color etc) and morphological properties of particles.

Scanning Electron Microscopy: It determines surface topography and type of crystals

(Polymorphism and crystal habit)

Hot Stage Microscopy: The polarizing microscope fitted with a hot stage or cold stage is an
extremely valuable tool for the characterization of polymorphic or solvate system.

Single Crystal X-ray Diffraction: Single crystal X – ray diffraction provides the most
complete information about the solid state. It will give information about the position of
molecular groups within the crystal and thus actually defines the differences between the
different forms.

Powder X – Ray Diffraction: Crystalline materials in powder form give characteristic X –

ray diffraction patterns made up of peaks in certain position and varying intensities.

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Differential Scanning Calorimetric (DSC): It measures the heat loss or gain resulting from
physical or chemical changes within a sample

Differential Thermal Analysis (DTA): It monitors the difference in temperature existing

between a sample and a reference as a function of temperature. It is useful in fusion, boiling,
sublimation, vaporization; crystalline structure inversion, solid-solid transition, and water loss
generally produce endothermic effects, and exothermic effects.

Thermo gravimetric analysis (TGA): It is a technique that measures changes in weight that
occur to a sample as function of temperature over time.

Fourier Transforms Infrared Spectroscopy (FT-IR): It is the identification of the drug

present and distinguishing between solvates and anhydrous form then for identifying
polymorphs.

Raman Spectroscopy: It is established technique for identifying and differentiating

pharmaceutical polymorphs.

Solid State NMR Spectroscopy: It is used to study crystalline solids, as well as

pharmaceutical dosage forms. It is used in the nature of polymorphic variations and
molecular conformations.

TYPES OF POLYMORPHISM [6]

Enantiotropy: In some cases one polymorphic form can change into another at a definite
temperature when the two forms have a common vapour pressure. This temperature is known
as the transition temperature. One form is stable above this temperature and the other form
below it. When the change of one form to the other at the tranaisition temperature is
revesible, the phenomenon is called Enantiotropy and the polymorphic forms enantiotropes.
For example, rhombic sulphur (α-sulphur) on heating changes to monoclinic sulphur (β-
sulphur) at 95.6ºc (transition temperature). Also monoclinic sulphur, on cooling, again
changes to rhombic sulphur at 95.6°c.

Monotropy: It occur when one form is stable and the other metastable. The metastable
changes to the stable form at all temperature and the change is not reversible. Thus there is no
transition temperature as the vapor pressures are never equal. This type of polymorphism is
exhibited by phosphorus.

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White phosphorus → red phosphorus

Another example is graphite and diamond, graphite being stable and diamond meta-stable,
although the change is infinitely slow.

Dynamic allotropy: Some substance has several forms which can coexist in equilibrium over
a range by the temperature. The separate forms usually have different molecular formulae but
the known as dynamic allotropy, resembles enantiotropy transition point. An example of
dynamic allotropy is provided by liquid sulphur which consist of three allotropes Sµ, SΠ ,Sλ.
These three forms of sulphur differ in molecular structure S λ is S8, SΠ is S4, while formula of
Sµ is not known. The composition of the equilibrium mixture at 120°c and 444.6°C (b.p of
sulphur) is,
120°c Sµ 0% SΠ 3.7 % Sλ 96.3%
444.6°c Sµ 37% SΠ 4% Sλ 59%

Table 5: Rules for Assigning the Nature of Phase Relationships in Polymorphic Systems
Rule Enantiotropic system
Fundamental Form 1 is the most stable
Definition polymorphic form at temperature
below the transition point, while
Form 2 is the most stable
polymorphic form at temperature
above the transition point
Heat of fusion The enthalpy of fusion of Form-1
is less than the enthalpy of fusion
of Form -2
Heat of The phase transition of Form-2 to
transition Form-1 is endothermic
Entropy of The melting points of both Form-1
fusion and Form-2 is less the temperature
of the transition point
Phase The phase transformation at the
transformation transition point is reversible.
Solubility Form -1 is most soluble
Polymorphic form at
Temperatures below the Transition
point, while Form-2 is the most
soluble Polymorphic form at
temperat
-ures above the transition point
Monotropic system
Form 1 is the stable polymorph at all
temperatures below that of the melting
point.
The enthalpy of fusion of Form-1 is
more than the enthalpy of fusion of
Form -2
The phase transition of Form-2 to
Form-1 is exothermic
The melting point of the most stable
polymorph is higher than the
temperature of the trans ion point
The phase transform ation of Form-2
into Form-1 is irreversible.
Form-1 is the most soluble polymorph
at all temperature below that of the
melting point.

Density The density of Form-1is less Than

The density of Form-1 is most than the
the density of Form-2
density of Form-2.

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POLYMORPHISM IN PHARMACEUTICALS
Structural science has played a large role in the field of chemistry and physics. Very early in
the 19th century it had become known that many compounds were capable of exhibiting the
phenomenon of Dimorphism and could be crystallized into solids having different melting
point and crystals habits. Robertson reported the structure of Resorcinol (1, 3-Dihydroxy
benzene). This crystalline material corresponded temperature and was later termed as α-
form. Shortly thereafter, it was found that α – form underwent a transformation into a denser
crystalline modification (denoted as the β – form). When heated to about 74°C and that the
structure of this newer form was completely different.

Table 4: Summary of the Unit Cell Parameters Associated with the two Polymorphs of
Resorcinol
Polymorphic form α – form β – form
Crystal class Orthorhombic Orthorhombic
Space group Pna Pna
Number of molecules per Unit cell Z=4 Z=4
a = 10.53 Aº a = 7.91 Aº
Unit cell axis lengths b = 9.53 Aº b = 12.57 Aº
c = 5.66 Aº c = 5.50 Aº
α = 90º α = 90º
Unit cell angles b = 90º b = 90º
γ = 90º γ = 90º

POLYMORPHISM IN NSAID
Ramesh panchagunlac et a[7]., found that the mefenamic acid (MA) has polymorphic Form I,
which converted to Form – II on heating in a DSC pan similarly compression in an intrinsic
dissolution rate (IDR) press resulted in the conversion of Form – I to Form – II, Who also
determined various techniques used for characterization included microscopy (hot stage
microscopy, Scanning electron microscopy), intrinsic dissolution rates, differential scanning
calorimetry (DSC), Fourier transform infrared (FTIR) spectroscopy and powder x-ray
diffractormetry (PXRD). F.Vrecer[8] found that piroxicam have three polymorphic forms and
one monohydrate form which was obtained by crystallization from saturated solutions in
various solvents. Polarity of solvents and crystallization rate defined by temperature of
crystallization were found to be critical parameters in determining the polymorphic Form A,
new polymorphic form designated as Form III was obtained by forced crystallization using
dry ice. The Form I having the highest melting point was found to be stable under mechanical
and thermal stress. Difference in dissolution rates among crystal forms of Piroxicam were

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attributed to difference in their wettability, where highest wettability was obtained for
monohydrate and the lowest for Form III.

Gray Nicholas[9] was found that paracetamol (acetaminophen) crystallization of the Form I
(monoclinic) and Form II (orthorhombic). He also analysed the characterization of single
crystal by x- ray diffraction, Powder x-ray diffraction, DSC, Thermo microscopy, optical
crystallography, scanning electron microscopy (SEM), compaction study. Palash Sanphui[10]
was found that nimesulide is an analgesic & anti pyretic activity. Form I of Nimesulide,
stability relationship, and characterization of polymorphs by Infra red (IR), Raman, SS-
nuclear magnetic Resonance (NMR), XRPD, & DSC. The crystal structure are stabilized by
N-H….O hydrogen bond and C-H…O,C-H….Π interaction. He also found that the intrinsic
dissolution and equilibrium solubility experiments showed that the meta stable Form II
dissolves much faster than the stable Form I. Guang Wel lu[11] was identified as Form I,
Form II and Form III with melting points of about 163,161.5, and 160.9°c. The
characterization of Celecoxib solid forms was analyzed by solubility, particle size,
dissolution, scanning electron microscopy with energy dispersive x-ray spectroscopy (SEM-
EDS), IR, Raman spectroscopy, DSC, PXRD, stability.

POLYMORPHISM IN ANTI-CONVULSANT
C.Rustichelli[12] was found that existence of three different polymorphic forms for anhydrous
carbamazepine. He also found that typical structure sensitive analytical techniques such as
FT-IR spectroscopy, XRPD and DSC.

POLYMORPHISM IN FLOURO QUINOLONES

R.Barbas[13] was identified Norfloxacin have two anhydrous polymorphs (Form A & Form
B). He also identified the characterization by DSC, thermogravimetry, PXRD, X-ray
13
structure determination, Raman spectroscopy, FTIR, solid state C NMR spectroscopy,
[14]
solvent mediated transformation experiments. Mange Ram Yadevc was found that five
different polymorph of Pefloxacin. Analytical techniques used for characterization of crystal
forms by microscopy, DSC, TGA, Gas chromatography (GC) Karl-fisher (KF) aquametry,
PXRD, IR, Microcalorimetry, Dissolution profile, Dissolution profile using MIC
determination by microbiological Assay.

CONCLUSION
The crystalline form and amorphous forms of drug molecules have similar chemical

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structure, molecular formula and molecular configuration, but differ in physico-chemical

properties like stability and solubility. To formulate the crystalline form of drug is very
difficult, but these formulation will be enough stable until its date of expiry. So, it is essential
to prepare and characterize the stable polymorph in the early stage of drug development.

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