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www.wjpps.com Vol 3, Issue 3, 2014. 621

Ethiraj et al. World Journal of Pharmacy and Pharmaceutical Sciences

POLYMORPHISM IN PHARMACEUTICAL INGREDIENTS

A REVIEW

*Ethiraj Thiruvengadam and Ganeshan Vellaisamy

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

ABSTRACT

When formulating a drug product, physico-chemical stability,

solubility and bio-availability of active pharmaceutical ingredient

(API) is an important impact. The knowledge of solid-state properties

of API in an early stage of drug development helps to avoid the

manufacturing defects and to improve its qualities. This makes the

study of polymorphism and crystallization of pharmaceutical

compounds highly important. Now-a-days, most of the drugs are

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 necessaryto 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 thathave different arrangements or conformations of the molecules in the crystal lattice.

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Article Received on

14 February 2014,

Revised on 28 February 2014

Accepted on 13 March 2014

*Correspondence for Author

Ethiraj Thiruvengadam

Department of Pharmaceutics,

The Erode College of

Pharmacy, Erode, Tamilnadu

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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 phases 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 moststable 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 dont 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 dont 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 rightangles.

Hexagonal

Four axes (three of which are identical in length and denoted as (a1, a2and

a3) lie in a horizontal plane, and are inclined to one another at 120. The

fourth axis, c, is different in length from the others, and is perpendicular to

the plane formed by the other three.

TetragonalThree axes (two of which are denoted as a1and a2, and are identical in

length) intersect at right angles. The third axis, c, is different in length with

respect to a1and 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.

MonoclinicThree axes (denoted as a, b, and c) of unequal length intersect, such that a

and c lie at an oblique angle, and the b axis is perpendicular to the plane

formed by the other two.

TriclinicThree axes (denoted as a, b, and c) of unequal length intersect At three

oblique angles.

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Table 2 : Crystals Grouped by Properties

Types Characteristics

Covalent

Crystals

A covalent crystal has true covalent bonds between all of the atoms in the

crystal. Many covalent crystals have extremely high melting points. Examples:

Diamond and Zinc sulfide crystals.

Metallic

Crystals

Individual metal atoms of metallic crystals sit on lattice sites. This leaves the

outer electrons of these atoms free to float around the lattice. Metallic crystals

tend to be very dense and have high melting points.

Ionic

Crystals

The atoms of ionic crystals are held together by electrostatic forces. Ionic

crystals are hard and have relatively high melting points. Examples: Sodium

chloride and Potassium chloride crystals.

Molecular

Crystals

These crystals contain recognizable molecules within their structures. A

molecular crystal is held together by non-covalent interactions, like van der

Waals forces or hydrogen bonding. Molecular crystals tend to be soft with

relatively low melting points. Examples: Rock candy, the crystalline form oftable 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

Packing properties

Molar volume and density

Refractive index

Conductivity: electrical and thermal

Hygroscopicity

Thermodynamic properties

Melting and sublimation temperatures

Internal or structural energy

Enthalpy

Heat capacity

Entropy

Free Energy and Chemical Potential

Thermodynamic Activity

Vapor Pressure

Solubility

Spectroscopic properties Electronic state transitionsVibration state transitions

Nuclear spin state transitions

Kinetic propertiesDissolution rate

Rates of solid-state reactions

Stability

Surface propertiesSurface free energyInterfacial 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 (-sulphur) on heating changes to monoclinic sulphur (-

sulphur) at 95.6c (transition temperature). Also monoclinic sulphur, on cooling, again

changes to rhombic sulphur at 95.6c.

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 S, S ,S.

These three forms of sulphur differ in molecular structure S is S8,Sis S4, while formula of

S is not known. The composition of the equilibrium mixture at 120c and 444.6C (b.p of

sulphur) is,

120c S0% S 3.7 % S 96.3%

444.6c S37% S4% S59%

Table 5: Rulesfor Assigning the Nature of Phase Relationships in Polymorphic Systems

Rule Enantiotropic system Monotropic system

Fundamental

Definition

Form 1 is the most stable

polymorphic form at temperature

below the transition point, while

Form 2 is the most stable

polymorphic form at temperatureabove the transition point

Form 1 is the stable polymorph at all

temperatures below that of the melting

point.

Heat of fusion The enthalpy of fusion of Form-1

is less than the enthalpy of fusion

of Form -2

The enthalpy of fusion of Form-1 is

more than the enthalpy of fusion of

Form -2

Heat of

transition

The phase transition of Form-2 to

Form-1 is endothermic

The phase transition of Form-2 to

Form-1 is exothermic

Entropy of

fusion

The melting points of both Form-1

and Form-2 is less the temperature

of the transition point

The melting point of the most stable

polymorph is higher than the

temperature of the trans ion point

Phasetransformation The phase transformation at thetransition point is reversible. The phase transform ation of Form-2into Form-1 is irreversible.

Solubility Form -1 is most soluble

Polymorphic form at

Temperatures below the Transition

point, while Form-2 is the mostsoluble Polymorphic form at

temperat-ures above the transition point

Form-1 is the most soluble polymorphat all temperature below that of the

melting point.

Density The density of Form-1is less Than

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

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 19thcentury 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 -

form. Shortly thereafter, it was found that form underwent a transformation into a denser

crystalline modification (denoted as the form). When heated to about 74C 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 form form

Crystal class Orthorhombic Orthorhombic

Space group Pna Pna

Number of molecules per Unit cell Z = 4 Z = 4

Unit cell axis lengths

a = 10.53 A

b = 9.53 A

c = 5.66 A

a = 7.91 A

b = 12.57 A

c = 5.50 A

Unit cell angles

= 90

b = 90

= 90

= 90

b = 90

= 90

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-HO,C-H. 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 160.9c. 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

structure determination, Raman spectroscopy, FTIR, solid state 13C NMR spectroscopy,

solvent mediated transformation experiments. Mange Ram Yadevc[14] 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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