Different Techniques and Characterization of Polymorphism with their Evaluation: A Review

Akshay R. Yadav*, Shrinivas K. Mohite

Department of Pharmaceutical Chemistry, Rajarambapu College of Pharmacy, Kasegaon,

Dist- Sangli, Maharashtra, India-415404.

*Corresponding Author E-mail: akshayyadav24197@gmail.com

ABSTRACT:

Polymorphism has emerged as a major focus for industry and regulatory agencies respectively. Polymorphism can affect physical and chemical stability, apparent solubility, dissolution, bioavailability and bioequivalence and drug product manufacturability, which require special attention during product development as it affects drug product quality, protection and effectiveness.It describes to exsist in two or more crystalline phases which have different arrangement of molecules in solid state with different arrangements or conformations of constituents in crystal lattices. The knowledge of the thermodynamic stability and thermokinetics is desired for better understanding of transformations and the time required for these transformations. Some of techniquesexamines difference in temperature form between reference and sample like function of temperature. It is useful in vapourization, boiling, fusion; solid-solid transition crystallization structure inversion and also used to characterize polymorphism to provide a powerful to isolate and identify of crystalline modification and its size and shape plays important role if they used as sustained release dosage. It usually have important role in properties like hardness of tablet and suspension stability and used to know difference between anhydrous and solvate form then for identification of polymorphs. Furthermore, the effect of polymorphism, polymorphism monitoring and regulation, and polymorphic knowledge reporting scheme in Abbreviated New Drug Application.

KEYWORDS: Dissolution, Bioavailability, Bioequivalence and New Drug Application.

INTRODUCTION:

Polymorphism fascinating phenomena of a chemistry and indeed is a difﬁcult concept studied from last many decades mainly and separately in the ﬁelds of inorganic and organic chemistry¹. Polymorphism comprises of two words in which poly means many and morphs means shapes so, it is defined as ability of molecule which exhibits two or more than two crystalline phases and these crystalline phases have different conformations and arrangements of the molecules in crystal lattice².

Table no. 1: Physical properties which reflects on parameter of crystal forms which given on following table:

Properties	Parameters
Thermodynamic properties	Solubility, sublimation, melting point, Enthalpy, entropy and vapour pressure
Kinetic properties	Dissolution rate
Surface properties	Interfacial tension and surface free energy
Packing properties	Refractive index, Hygroscopitcity, Molar volume and density
Mechanical properties	Tensile strength and hardness
Spectroscopic properties	Vibration state transition Nuclear spin state transition Electric state transition

Role of polymorphism in pharmaceutical:

1. Different forms exhibited by each drugs and they have distinct physical and chemical properties like dissolution rate, optical, electrical properties, melting point, stability, solubility, density and vapour pressure.

2. These proportion reflected with manufacturing of drug then drug product and then dissolution rate, stability and bioavailability of drug product.

3. It is one of the effective element in drug development.

4. Major challenges in characterization, differentiating and isolation of polymorphs.

5. It is common among pharmaceutical substances and thermodynamic stability which have influence on properties like process ability, manufacturabilitiy and bioavailability³.

Types of polymorphism:

1. Monotropy:

It generally occur if one form is stable and other is metastable and further it changes to metastable forms in all temperature and change is not reversibleso there is no transition temperature then vapour pressure is not equal. Example such as Niccerogoline which is potent blocking agents exhibits two forms such as orthorhombic and triclinic forms. In contrast, graphite is the only stable solid allotrope of carbon, and at all temperatures diamond is very, very slow in changing into graphite. Any such pair of allotropes is said to be monotropic if only one form is stable over the whole range of temperatures. It may, therefore, seem strange that diamond shows a greater resistance to chemical attack and has a stronger molecular structure. All the differences between the two allotropes may be attributed to the distinct arrangements of the carbon atoms in space. In diamonds each carbon atom is linked by valence bonds of equal length to four adjacent carbon atoms, so that the diamond lattice extends in all three dimensions. Graphite has a plate-like structure – each carbon atom is linked to three more carbon atoms in the one plane while the fourth much longer bond forms a weak link with an atom in the next plane. Thus the valence bonds in graphite do not hold the carbon atoms together so tightly as they do in diamond – compare the result of drawing a piece of graphite (pencil "lead") and diamond across a sheet of paper. The hard diamond bites into the paper whereas the graphic crystals shear off in layers. The structure accounts also for the higher electrical conductivity of graphite. Likewise graphite, although comparatively unreactive, takes part in chemical reactions more readily than diamond. If heated sufficiently in air or oxygen, both allotropes yield carbon dioxide and there is no difference between the molecules of this gas formed from the two allotropes⁴.

2. Dynamic allotropy:

Some drugs have various forms coexist over a range by temperature and separate forms having different formulae resembles enantiotrpy transition point reffered as dynamic allotropy. The proportion of the two allotropes that are in equilibrium with one another varies with temperature and sometimes with pressure. The two liquid forms of sulfur exhibit this type of allotropy, and the change from one form to the other is accompanied by a change in color and its viscosity (resistance to flow). As sulfur is heated above its melting point, the amber mobile liquid becomes darker in color and much more viscous (thick). The viscosity reaches a maximum at about 180°C. Further heating produces a much darker, almost black, liquid which gradually becomes less viscous. The two liquid allotropes are called λ-sulfur and μ-sulfur. At temperatures close to the melting point the proportion of λ-sulfur is quite high, but as the temperature rises more and more of the λ-form changes into μ-sulfur. The molecules of both forms contain eight atoms arranged in a ring, which ruptures on heating to yield chains still containing eight atoms. which ruptures on heating to yield chains still containing eight atoms. Theincrease in viscosity at 180°C is attributed to their interaction between these chains⁵.

3. Enantiotropy:

When one form is stable and other form below at transition temperature is reffered as enantiotropy. Example such as rhombic sulphur which on heating changes to monoclinic sulphur.In the solid state sulfur can exist in two different crystalline allotropes – rhombic and monoclinic At temperatures below 95.5°C the rhombic form is stable, and any needle-shaped crystals of monoclinic sulfur which cool below this temperature will be gradually converted into the rhombic form. Conversely, the monoclinic form is stable between 95.5°C and the melting point (119.25°C), and when maintained at a temperature in this range the rhombic form slowly changes into monoclinic. However, if rhombic sulfur is heated rapidly it will melt at 112.8°C to yield an amber-colored liquid. Rhombic and monoclinic sulfur are said to be enantiotropic allotropes, since one form is stable below a certain definite temperature or transition point while the second form is stable above this temperature. As the names of these two allotropes imply, the principal difference between them is in their crystalline structures⁶.

Methods used for authentic polymorphic forms⁷:

1. Heating procedure

2. Crystallization from melting

3. Thermal desolvation of crystalline solvates

4. Crystallization by using mixture of solvents

5. Milling and griding

6. Rapidly changing solution of pH to precipitate acidic or basic substances

7. Sublimation

8. Vapour diffusion

9. By using some Additives

Characterization of polymorphs:

There are different techniques have been used to characterize polymorphism to provide a powerful to isolate and identify of crystalline modification.

1. Differential thermal Analysis (DTA):

It examines difference in temperature form between reference and sample like function of temperature. It is useful in vapourization, boiling, fusion; solid-solid transition crystallization structure inversion etc. It is a thermoanalytic technique that is similar to differential scanning calorimetry. In DTA, the material under study and an inert reference are made to undergo identical thermal cycles, while recording any termperature difference between sample and reference. The differential temperatures istheb plotted against time, or against temperature. Changes in the sample, either exothermic or endothermic, can be detected relative to the inert reference. Thus, a DTA curve provides data on the transformations that have occurred, such as glass transitions, crystallization, melting and sublimation⁸.

2. Raman spectroscopy:

It is used to differentiate and identify polymorphs. Raman spectroscopy is a non-destructive chemical analysis technique which provides detailed information about chemical structures, phase and polymorphy, crystallinity and molecular interactions. It is based upon the interaction of light with the chemical bonds within a material. Modern Raman spectroscopy nearly always involves the use of lasers as excitation light sources. Because lasers were not available until more than three decades after the discovery of the effect, Raman and Krishnan used a mercury lamp and photographic plates to record spectra. Early spectra took hours or even days to acquire due to weak light sources, poor sensitivity of the detectors and the weak Raman scattering cross-sections of most materials. Various colored filters and chemical solutions were used to select certain wavelength regions for excitation and detection but the photographic spectra were still dominated by a broad center line corresponding to Rayleigh scattering of the excitation source. Technological advances have made Raman spectroscopy much more sensitive, particularly since the 1980s. The most common modern detectors are now charge-coupled devices (CCDs). Photodiode arrays and photomultiplier tubes were common prior to the adoption of CCDs. The advent of reliable, stable, inexpensive lasers with narrow bandwidths has also had an impact.

3. Solid state NMR spectroscopy:

It used to know molecular conformations, polymorphic variations, crystalline solids and pharmaceutical dosage forms. Solid-state NMR (ssNMR) spectroscopy is a special type of nuclear magnetic resonance (NMR) spectroscopy, characterized by the presence of anisotropic (directionally dependent) interactions. Compared to the more common solution NMR spectroscopy, ssNMR usually requires additional hardware for high-power radio-frequency irradiation and magic-angle spinning⁹.

4. Scanning electron microscopy:

It a type of electron microscope that produces images of a sample by scanning the surface with a focused beam of electrons. The electrons interact with atoms in the sample, producing various signals that contain information about the surface topography and composition of the sample. The electron beam is scanned in a raster scan pattern, and the position of the beam is combined with the intensity of the detected signal to produce an image. In the most common SEM mode, secondary electrons emitted by atoms excited by the electron beam are detected using a secondary electron detector (Everhart-Thornley detector). The number of secondary electrons that can be detected, and thus the signal intensity, depends, among other things, on specimen topography. SEM can achieve resolution better than 1 nanometer. It used to determine type of crystal i.e crystal polymorphism and crystal habits.

5. Fourier transformer infrared spectroscopy (FT-IR):

It used to identify difference between anhydrous and solvate form then for identification of polymorphs. FTIR is a technique used to obtain an infrared spectrum of absorption or emission of a solid, liquid or gas. An FTIR spectrometer simultaneously collects high-spectral-resolution data over a wide spectral range. This confers a significant advantage over a dispersive spectrometer, which measures intensity over a narrow range of wavelengths at a time¹⁰.

6. Hot stage microscopy:

It is fitted with cold or hot stage is an analytical tool to characterize solvate system or polymorphic form. A hot-stage microscope was constructed by Welch in the 1950s. Using such a device it is possible to observe and record (photographic or digital recording) the changes of sample contours with temperature, which makes possible to determine fusibility (from the sample shape and geometry), and also viscosity, wettability and surface tension of various raw materials and products at the temperatures approximating the range of their melting. Modern hot-stage microscopes provide a continuous recording of such measurements and a computer-aided handling of laboratory data. As a method is simple, and its results are of a considerable practical significance.

7. Thermogravimetric analysis (TGA):

TGA is a method of thermal analysis in which the mass of a sample is measured over time as the temperature changes¹¹.

8. Powder X-ray diffraction:

It give characteristic X-ray diffraction patterns peaks in some position and different intensities. Powder diffraction is a scientific technique using X-ray, neutron, or electron diffraction on powder or microcrystalline samples for structural characterization of materials. An instrument dedicated to performing such powder measurements is called a powder diffractometer¹⁷.

9. Single crystal X-ray diffraction:

X-Ray single-crystal diffraction has been the most straightforward and important technique in structural determination of crystalline materials for understanding their structure–property relationships. This powerful tool can be used to directly visualize the precise and detailed structural information of porous coordination polymers or metal–organic frameworks at different states, which are unique for their flexible host frameworks compared with conventional adsorbents. With a series of selected recent examples, this review gives a brief overview of single-crystal X-ray diffraction studies and single-crystal to single-crystal transformations of porous coordination polymers under various chemical and physical stimuli such as solvent and gas sorption/desorption/exchange, chemical reaction and temperature change¹².

Applications:

1. Enhanced physical stability:

Crystal forms usually have important role in properties like hardness of tablet and suspension stability which can be done by using glycerol and absolute alcohol with help of this solubility can be enhanced¹³.

2. Impact on bioavailability:

There are some drugs wichshow properties on crystalline form for example penicillin G and its unwanted degradation in GI fluid can be avoid by its crystalline form.

3. Sustained release:

Its size and shape plays important role if they used as sustained release dosage for e.g, protamine zinc insulin.

4. Purification of drugs:

Isolation of impurities by recrystallization traditional techniques i.e crystallization of drug substance is used.

5. Handling of drug:

Drug when introduced in body so handling of drug substances and formulations is important and similarly type of packing.

6. Better chemical stability:

Stability is enhanced by crystallization like crystalline salts is more stable than amorphous penicillin G¹⁴.

CONCLUSION:

Polymorphism can affect physical and chemical stability, apparent solubility, dissolution, bioavailability and bioequivalence and drug product manufacturability, which require special attention during product development as it affects drug product quality, protection and effectiveness. It describes to exsist in two or more crystalline phases which have different arrangement of molecules in solid state with different arrangements or conformations of constituents in crystal lattices. Formulation by using crystalline form is very difficult but it is quiet stable as compare to amorphous form on shelf life, thus mostly stable form gives preference at the time of formulation.

ACKNOWLEDGEMENT:

I express my sincere thanks to Vice-principal Prof. Dr. S. K. Mohite for providing me all necessary facilities and valuable guidance extended to me.

REFERENCES:

1. Panchagnula R, Sundramurthy P, Pillai O, Shrutidevi A, Yasvanth A. Solid State Characterization of Mefenamic Acid. Journal of Pharmaceutical Science. 2004;93(4):1019-1029.

2. Cesur S, Gokbel S. Crystallization OfMefenamic Acid and Polymorphs. Crystal Research Technology 2008;43(7):720-728.

3. Hosokawa K, Goto J, Hirayama N. PredicitionOf Solvents Suitable for Crystallization Of Small Organic Molecules. Chemical and Pharmaceutical Bulletin. 2005;53(10):1296-9.

4. Manavalan R, Ramasamy C. Physical Pharmaceutics. VigneshPublisher, India 2004: 20 -43.

5. Bahl B, Tuli G, Bahl A, Essential of Physical Chemistry. Twenty-Fourth, India.1997: 565.

6. Vrecer F, Srcic S, Korbar S. Investigation OfPiroxicam Polymorphism. International Journal of Pharmaceutics. 1991;68: 3541.

7. Gary N, Christopher S. Physico-Chemical Characterization of The Orthorhombic Polymorph of Paracetamol Crystallized from Solution. Journal of Pharmaceutical Science. 1998;87: 684-693.

8. Bauer, J, Spanton, S, Henry R, Quick J, Dziki W, Porter W, Morris J. Ritonavir: An Extraordinary Example of Conformational Polymorphism. Pharm. Res. 2001; 18: 859–866.

9. Threlfall T. Analysis of Organic Polymorphs. A Review. Analyst 1995; 120: 2435–2460.

10. Haleblian J, Mccrone W. Pharmaceutical Applications of Polymorphism. Journal of Pharmaceutical sciences. 1995; 58: 911–929.

11. Stahly, G. Diversity in Single- And Multiple-Component Crystals. The Search for and Prevalence of Polymorphs and Cocrystals. Cryst. Growth Des. 2007; 7:1007–1026.

12. Taylor L, Langkilde F. Evaluation of Solid-State Forms Present in Tablets By Raman Spectroscopy. Journal of Pharmaceutical sciences. 2000; 89:1342–1353.

13. Santos O. Polymorphism: An Evaluation of The Potential Risk to The Quality of Drug Products from The Famacia Popular RedePropria. British journal of pharmacology. 1994; 25 :1984-1989.

14. Farias M and Carneiro R, Simultaneous Quantification of Three Polymorphic Forms of Carbamazepine In The Presence Of Excipients Using Raman Spectroscopy. Molecules 2014; 19: 14128-14138.

Received on 02.03.2020 Modified on 16.04.2020

Asian J. Pharm. Tech. 2020; 10(3):213-216.

DOI: 10.5958/2231-5713.2020.00035.5